CN102811619A

CN102811619A - Kinase inhibitors

Info

Publication number: CN102811619A
Application number: CN2010800515489A
Authority: CN
Inventors: 李宰圭; 宋浩俊; 高钟声; 李熙圭; 金泳三; 金洪宇; 张纯花; 林顺熙; 崔章植; 金正皓; 金世源
Original assignee: Oscotec Inc; Genosco
Current assignee: Oscotec Inc; Genosco
Priority date: 2009-11-13
Filing date: 2010-11-12
Publication date: 2012-12-05
Anticipated expiration: 2030-11-12
Also published as: MY160820A; IL219726A0; MX2012005332A; EP2498607A4; EP2498607B1; HK1179477A1; US8629132B2; CN102811619B; JP2013510876A; BR112012011287A2; IL219726A; CL2012001221A1; JP5740409B2; KR20130006417A; BR112012011287B1; AU2010319382A1; KR101663637B1; EP2498607A1; EA201290324A1; SG10201407453TA

Abstract

The present invention provides a new group of protein kinase inhibitors, pyrropyrimidine and pyrazolopyrimidine derivatives, and pharmaceutically acceptable salts and prodrugs thereof that are useful for treating cell proliferative disease and disorder such as cancer, autoimmune diseases, infection, cardiovascular disease and neurodegenerative disease and disorder. The present invention provides methods for synthesizing and administering the protein kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor. The invention also provides useful intermediates generated during the syntheses of the pyrropyrimidine and pyrazolopyrimidine derivatives.

Description

Inhibitors of kinases

Related application

The right that No. the 61/261st, 100, the U.S. Provisional Application that the application requires to propose on November 13rd, 2009.The full content of said application is incorporated this paper into way of reference.

Background technology

Protein kinase comprises relevant phosphoryl transferase on the big group structure, and this phosphoryl transferase is transferred to the terminal-phosphate catalysis of adenosine triphosphate (ATP) on the hydroxyl of tyrosine, serine and/or threonine residues of albumen.According to the substrate of phosphorylation, can protein kinase be divided into several types, for example protein tyrosine kinase (PTK) and albumen serine/threonine kinase.

Through changing enzymic activity, celluar localization or related with other albumen,, can make kinase whose target protein (substrate) that the variation on the function takes place via the phosphorylation of protein kinase.Protein kinase is not only being played the part of extremely important role aspect growth of control cell and the differentiation, and in a lot of intracellular signal transduction pathway, also plays extremely important regulating action.Wherein protein kinase can effectively be regulated growth factor and such as TNF (TNF)-various production of cytokines such as α.The instance of albumen-EGFR-TK comprise SYK, PYK2, FAK, ALK, AXL, CSF1R, FLT3, JAK2 (JH1 domain-catalysis), JAK3 (JH1 domain-catalysis), KIT, KIT (D816V), KIT (V559D, T670I), PDGFRB, RET, TYK2 and ZAP70.The instance of albumen-serine/threonine kinase comprises PIM1, AURKA, AURKB, BMPR2, JNK1, JNK2, JNK3, LKB1, LRRK2, LRRK2 (G2019S), MLK1, PAK4, PLK4, RSK2 (Kin.Dom.1-N-is terminal), SNARK, SRPK3 and TAK1.

The mistake adjusting of these protein kinases can relate to multiple disease and obstacle disease; For example central nervous system disorder (for example; Alzheimer disease (Alzheimer ' s disease)), struvite and autoimmune disease (for example; The easy sharp sick and psoriasis of asthma, rheumatoid arthritis, Crohn's disease (Crohn ' s disease) and inflammatory bowel), bone disease (for example; Osteoporosis), metabolic disorder (for example, diabetes), vascular proliferative disease, illness in eye, cardiovascular disease, cancer, restenosis, pain, graft rejection and infectious diseases.Although understood the biology of protein kinase and importance clinically in the industry, but still need the kinase whose compound of CKIs, think relevant or effective and safe clinical treatment is provided by the disease of its mediation with protein kinase.In the industry also need be to the method that has the patient that needs or experimenter to use this compound, pharmaceutical preparation and medicament.

Summary of the invention

The invention provides mixture or its pharmaceutically acceptable salt of a kind of formula I compound or its single stereoisomer, isomer,

Formula I

Wherein:

X is CH or N;

R ¹Be selected from H, halogen, CN, C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) alkyl, wherein C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) alkyl can be through randomly replacing;

R ²Be aryl, cycloalkyl, aryl alkyl or heterocyclic radical, wherein said aryl, cycloalkyl, aryl alkyl or heterocyclic radical optional and independently at one or more carbon atoms place through 1-4 R ⁵Or R ^5aGroup replaces; And the aryl and the heterocyclic radical that wherein contain one or more nitrogen-atoms are optional and independently at one or more nitrogen-atoms place through 1-4 R ⁶Or R ^6aGroup replaces;

R ³Be halogen, CN or R independently ⁷And

R ⁴Be selected from (CH ₂) _nOH, (CH ₂) _nNR ¹¹R ¹², C (O) NHR ⁷, C (O) NR ¹¹R ¹², C (O) OR ⁷, C (O) R ⁷, C (O) NR ⁷R ⁷, C (O) NR ⁷R ⁸, (CH ₂) _nNR ⁷R ⁷, (CH ₂) _nNR ⁷R ⁸, (CH ₂) _nCN, (CH ₂) _nSR ⁷, (CH ₂) _nS (O) _nR ⁷, or (CH ₂) _nS (O) _nNR ⁷R ⁷, wherein each n is 1 or 2 all independently;

Wherein:

Each R ⁵Be independently selected from halogen, CF ₃, SR ⁷, OR ⁷, OC (O) R ⁷, O (CH ₂) _nNR ⁷R ⁷, O (CH ₂) _nNR ¹¹R ¹², O (CH ₂) _nR ⁷, O (CH ₂) _nC (O) NR ¹¹R ¹², O (CH ₂) _nC (O) NR ⁷R ⁷, NR ⁷R ⁷, NR ⁷R ⁸, NHC (O) NH ₂, C (O) OR ⁷, NO ₂, CN, C (O) R ⁷, OSO ₂CH ₃, S (O) _nR ⁷, S (O) _nNR ⁷R ⁷, NR ⁷C (O) NR ⁷R ⁷, NR ⁷C (O) R ⁷, NR ⁷C (O) OR ⁷, NR ⁷S (O) _nR ⁷, or NR ¹¹R ¹², wherein each n is 1 or 2 all independently;

Each R ^5aBe independently selected from amino, halogen, hydroxyl, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, alkoxyl, haloalkyl, aryl, heteroaryl or heterocyclic radical, wherein said C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, alkoxyl, haloalkyl, aryl, heteroaryl or heterocyclic radical are optional and be selected from halogen, hydroxyl, alkyl, R through 1-3 independently ⁹, or R ¹⁰Group replace;

Each R ⁶Be R independently ⁷, C (O) CH ₂CN, C (O) R ⁷, C (O) OR ⁷, CO ₂(C ₁-C ₆Alkyl), C (O) NR ⁷R ⁷, SO ₂NR ⁷R ⁷, or SO ₂R ⁷

Each R ^6aBe hydroxyl, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, haloalkyl, wherein each R ^6aGroup is optional and be selected from hydroxyl, aryl, alkyl, halogen, R through 1-3 independently ⁹, or R ¹⁰Group replace;

Each R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, aryl (C ₁-C ₄) alkyl, haloalkyl, heteroaryl or heterocyclic radical, wherein said C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, aryl (C ₁-C ₄) alkyl, haloalkyl, heteroaryl or heterocyclic radical is optional and be selected from aryl, cycloalkyl, heteroaryl, heterocyclic radical, alkyl, halogen, amino, hydroxyl, R through 1-4 independently ⁹, or R ¹⁰Group replace;

Each R ⁸Be C (O) R independently ⁷, C (O) OR ⁷, C (O) NR ⁷R ⁷, or S (O) _nR ⁷, wherein n is 1 or 2;

Each R ⁹Be CF independently ₃, SR ⁷, OR ⁷, NR ⁷R ⁷, NR ¹¹R ¹², C (O) NR ⁷R ⁷, C (O) NR ¹¹R ¹², S (O) _nNR ⁷R ⁷, or S (O) _nR ⁷, wherein each n is 1 or 2 all independently;

Each R ¹⁰Be C (O) O (C ₁-C ₆) alkyl or halo (C ₁-C ₄) alkyl; And

R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms:

I) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot, wherein said 3-8 unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace;

Ii) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot; A wherein said 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace;

Iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace;

Iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein said hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide; Or

V) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; A wherein said 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace;

Or its pharmaceutically acceptable salt.

In some aspects, R ¹Be selected from H, F, Cl, Br, CF ₃, or CH ₃R ¹Randomly through replacing.

In some aspects, R ²Be aryl, cycloalkyl, aryl alkyl or heterocyclic radical.Said aryl, cycloalkyl, aryl alkyl or heterocyclic radical optional and independently at one or more carbon atoms place through 1-4 R ⁵Or R ^5aGroup replaces.In one embodiment, R ²Can be aryl, and said aryl randomly at one or more carbon atoms place through 1-4 R ⁵Or R ^5aGroup replaces.R ²Aryl can be and contain one or more heteroatomic heteroaryls, said hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone.R ²Heteroaryl and heterocyclic radical can contain one or more nitrogen-atoms, said nitrogen-atoms is optional and independently through 1-4 R ⁶Or R ^6aGroup replaces.R ²Aryl can be (for example): contain the heteroatomic 5-6 of 0-3 unit monocyclic aryl, wherein hetero atom is independently selected from nitrogen, oxygen or sulphur; Contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Contain 0-5 the undersaturated aryl bicyclic of heteroatomic 8-10 unit's part, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Or, contain the undersaturated aryl bicyclic of 8-10 unit part of formamide or sulfonamide.

In one embodiment, R ²Aryl be 5-6 unit monocyclic aryl, for example phenyl, pyrimidine radicals or pyridine radicals, said monocyclic aryl is optional and be selected from following group through 1,2 or 3 independently and replace: methyl, ethyl, phenyl, 2-hydroxyl-oxethyl, isopropyl, methoxyl group OC ₆H ₅, OCH ₂C ₆H ₅, OCH ₂CH ₂NR ¹¹R ¹², OCH ₂CH ₂NR ⁷R ⁷, OCH ₂C (O) NR ¹¹R ¹², OCH ₂C (O) NR ⁷R ⁷, CF ₃, OSO ₂CH ₃, SO ₂CH ₃, SO ₂NHCH ₃, or NR ¹¹R ¹²

In another embodiment, R ²Be to contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur or sulfoxide.R ²Aryl bicyclic be selected from indyl, indazolyl, naphthyl or quinolyl, and optional and be selected from following group replacement at commutable carbon atom or 1,2 or 3 at nitrogen-atoms place independently: alkyl, alkoxyl, halogen, aryl, heteroaryl, cycloalkyl, CF ₃, OCF ₃, C (O) alkyl, C (O) aryl, S (O) ₂Alkyl; Wherein alkyl, aryl or heteroaryl randomly replace through hydroxyl, amino or sulfone.

In another embodiment, R ²Be the aryl bicyclic that contains 0-5 the first fractional saturation of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone.For example, the bicyclic groups of 8-10 unit fractional saturation is dihydrobenzo bioxin base, tetralyl or dihydro indenyl, and optional and independently at substitutable carbon atom place 1,2 or 3 be selected from alkyl, aryl, heteroaryl, alkoxyl, halogen, CF ₃, OCF ₃, or SO ₂CH ₃Group replace.

In some aspects, R ³Be H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

In one embodiment, R ⁴Be C (O) OR ⁷, and R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical.C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical are optional and be selected from hydroxyl, halogen, amino, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.For example, R ⁷Be H or C independently ₁-C ₁₀Alkyl.In addition, R ⁷C ₁-C ₁₀Alkyl can be chosen wantonly and be selected from halogen, hydroxyl, amino, C through 1-4 independently ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

In one embodiment, R ⁴Be C (O) R ⁷, and C (O) R ⁷R ⁷Be C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl or, heterocyclic radical, wherein R ⁷Optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.For example, R ⁷Can be independently selected from H or C ₁-C ₁₀Alkyl.R ⁷C ₁-C ₁₀Alkyl can be chosen wantonly and be selected from halogen, hydroxyl, amino, C through 1-4 independently ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

In one embodiment, R ⁴Be C (O) NHR ⁷, and R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₄-C ₁₂Cycloalkenyl group, aryl, aryl alkyl, haloalkyl or heterocyclic radical.C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₄-C ₁₂Cycloalkenyl group, aryl, aryl alkyl, haloalkyl or heterocyclic radical are optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.In one embodiment, R ⁷Can be selected from C ₁-C ₁₀Alkyl or aryl.Aryl can be phenyl, and this phenyl is optional and be selected from methyl, methoxyl group, hydroxyl, OC (O) R through 1,2 or 3 independently ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, C (O) NHR ⁷, CF ₃, or SO ₂CH ₃Group replace.Preferred substituted is methyl, methoxyl group, CF ₃, and SO ₂CH ₃R ⁷C ₁-C ₁₀Alkyl is optional and be selected from amino, halogen, hydroxyl, phenyl, phenylalkyl, C through 1-4 independently ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

In one embodiment, R ⁴Be C (O) NR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot, wherein 3-8 unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace; (ii) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace; (iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, do not contain the first saturated or fractional saturation two of heteroatomic 9-10 the wherein said nitrogen-atoms that removes institute's key knot and encircle and randomly independently be selected from R through 1-4 at one or more substitutable carbon atoms place ⁵Or R ^5aGroup replace; Or, (iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.For example, it is saturated or the fractional saturation ring can be chosen wantonly and independently through 1-4 hydroxyl or amino replacement wherein except that the nitrogen-atoms of institute key knot, not contain heteroatomic 3-8 unit.

In one embodiment, R ⁴Be (CH ₂) _nNR ⁷R ⁷(CH ₂) _nNR ⁷R ⁷R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl or heterocyclic radical.(CH ₂) _nNR ⁷R ⁷R ⁷Optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.For example, R ⁷Can be H, C independently ₁-C ₁₀Alkyl, C ₃-C ₁₂Cycloalkyl, aryl or heterocyclic radical, and this R ⁷Optional and replace through 1-4 group that is selected from hydroxyl, amino, aryl, alkyl or halogen independently.In one embodiment, R ⁷Be H or C independently ₁-C ₁₀Alkyl.C ₁-C ₁₀Alkyl randomly replaces through phenyl.Phenyl can be chosen wantonly and replace through one or more alkyl, halogen, amino or hydroxyl independently.

In certain aspects, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot, wherein said 3-8 unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace; (ii) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace; (iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace; (iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide; Or, (v) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Remove R with a nitrogen-atoms-formation of their institute's key knots ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot.Except that the nitrogen-atoms of institute key knot, do not contain heteroatomic 3-8 unit saturated or the fractional saturation ring optional and independently at one or more substitutable carbon atoms place through the individual R that is selected from of 1-4 ⁵Or R ^5aGroup replace.Except that the nitrogen of institute key knot, do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit and can be 4,5 or 6 yuan of saturated rings, these 4,5 or 6 yuan of saturated rings choose wantonly and independently at one or more substitutable carbon atoms place through one or more hydroxyls, OC (O) R ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, or C (O) NHR ⁷Replace.Preferably, 3-8 unit ring is selected from azelidinyl (azetidinyl), pyrrolidinyl or piperidyl, its optional and independently at one or more substitutable carbon atoms place through hydroxyl, halogen, OC (O) R ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, or C (O) NHR ⁷Replace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot.Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.For example, the heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring is to contain 1 heteroatomic 6 yuan or 7 yuan of saturated rings.Hetero atom can be nitrogen, and randomly through C ₁-C _I0Alkyl, hydroxyl C ₂-C ₁₀Alkyl or C (O) NHR ⁷Replace.Perhaps, hetero atom can be oxygen.In one embodiment, oxygen and R ¹¹, R ¹²And and R ¹¹, R ¹²The nitrogen-atoms of institute's key knot can form morpholinyl.Saturated or the fractional saturation ring of the heteroatomic 5-8 of the said 1-3 of containing unit can be morpholinyl, thiomorpholine base, piperazinyl or high piperazinyl.Piperazinyl or high piperazinyl optional and independently at the nitrogen-atoms place through hydroxyl, C ₁-C ₁₀Alkyl, CH ₂CH ₂OH, C (O) R ⁷, C (O) NHR ⁷, SO ₂R ⁷, SO ₂NHR ⁷, or C (O) OR ⁷Replace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot.Said except that the nitrogen-atoms of institute key knot, do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit randomly at one or more substitutable carbon atoms place through the individual R that is independently selected from of 1-4 ⁵Or R ^5aGroup replace.For example, said two rings can form tetrahydroisoquinoline.Said two rings also can contain aryl at ring.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot.Wherein 1-5 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.Saturated or fractional saturation two rings of the heteroatomic 9-10 of the said 1-5 of containing unit can be chosen wantonly and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.Said two rings also can contain aryl at ring.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

The invention still further relates to: comprise these compound compositions; The method for preparing these compounds; Through using these compound inhibitory enzyme activities, especially suppress the method for SYK, PYK2, FAK, ZAP70, PIM1, RET, FLT3, JAK2 and LRRK2 kinase activity; And, be the method for mammal treatment disease or disease syndrome, wherein especially can be through suppressing the effect of kinase activity influence treatment disease.

Formula (I) compound is used to suppress one or more protein kinases, and is used to treat by protein kinase mediated disease and obstacle disease, for example cancer, autoimmune disease, infection, cardiovascular disease and nerve degenerative diseases.

In one aspect, the invention provides pharmaceutical composition, this pharmaceutical composition comprises formula (I) compound and pharmaceutically acceptable carrier.In certain embodiments, these pharmaceutical compositions through allotment to carry out administration in administration in intravenous administration, subcutaneous administration, suction, oral administration, rectally, parenterai administration, glass vivo medicine-feeding, intramuscular administration, intranasal administration, percutaneous dosing, topical, the ear, eye drops, the cheek, tracheae administration, bronchi administration or through sublingual administration.In other embodiments, said pharmaceutical composition is deployed into lozenge, pill, capsule, liquid, inhalant, nasal spray, suppository, solution, gel, emulsion, ointment, eye drops or auristilla.

In one aspect; The invention provides in vivo (in vivo) or the in vitro method of (in vitro) inhibition SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2 signal transduction, this method comprises compound according to claim 1 from effective dose to said experimenter that use.

In one aspect; The invention provides the method for the treatment cell proliferation disorders or the patient's condition (for example cancer); This method comprises that wherein the cell proliferation disorders or the patient's condition comprise (for example) lymphoma, osteosarcoma, melanoma, breast cancer, kidney, prostate cancer, colorectal cancer, thyroid cancer, oophoroma, cancer of pancreas, neural cancer, lung cancer, the cancer of the uterus or human primary gastrointestinal cancers to formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition or the medicament of experimenter's administering therapeutic effective dose that these treatment needs are arranged.In one aspect, the invention provides the method for using compound according to claim 1 or the growth of its pharmaceutically acceptable salt anticancer.

On the other hand; The invention provides the medicament for disease, obstacle disease or the patient's condition of patient treatment SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2-mediation, this medicament comprises formula (I) compound of treating effective dose.

On the other hand; The invention provides the purposes of a kind of formula (I) compound in making medicament, wherein said medicament is used to treat disease, obstacle disease or the patient's condition of SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2-mediation.

On the other hand, the invention provides the kinase whose method of CKIs, this method comprises to formula (I) compound of experimenter's administering therapeutic effective dose that needs are arranged or its pharmaceutically acceptable salt or its pharmaceutical composition.Said protein kinase includes, but is not limited to SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2 kinases.

On the other hand, the invention provides the kinase whose method of CKIs, this method comprises makes cell contact with formula (I) compound.In certain embodiments; Formula (I) compound can effectively suppress one or more kinase whose activity; Wherein said kinases be selected from SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2.

On the other hand; The invention provides the protein kinase mediated disease of treatment or the method for the patient's condition, this method comprises formula (I) compound or its pharmaceutically acceptable salt or its pharmaceutical composition or the medicament to experimenter's administering therapeutic effective dose that these treatment needs are arranged.Said protein kinase include, but is not limited to SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2.

In certain embodiments; The protein kinase mediated disease or the patient's condition are diseases associated with inflammation or the patient's condition, RD or autoimmune disease or the patient's condition, for example asthma, COPD (COPD), adult respiratory distress syndrome (ARDS) (ARDS), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, chorionitis, nettle rash, rheumatoid arthritis, multiple sclerosis, cancer, breast cancer, AIDS virus (HIV) relevant disease or lupus.

On the other hand, the invention provides the method for treating the nerve/nerve degenerative diseases or the patient's condition through to formula (I) compound or its pharmaceutically acceptable salt of experimenter's administering therapeutic effective dose.In certain embodiments, the said nerve/nerve degenerative diseases or the patient's condition comprise (for example) Alzheimer disease, encephaledema, cerebral ischemia, multiple sclerosis, neuropathy, Parkinson's, blunt wound or operation wound (comprising operation back cognition dysfunction and spinal cord or brain-stem injury) and neurological disease (for example degenerative disc disease and sciatica).

On the other hand, the invention provides the method for treating cardiovascular disease through to formula (I) compound or its pharmaceutically acceptable salt of experimenter's administering therapeutic effective dose.Wherein, Said cardiovascular disease influences heart or blood vessel, and comprises (for example): reperfusion injury, endotoxin induction or operation or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vessel retraction, aberrant angiogenesis or inflammation around atherosclerotic, arrhythmia, pharyngalgia, myocardial ischemia, miocardial infarction, heart or vascular knurl, vasculitis, apoplexy, limbs or the organ or tissue behind obstructive arteriopathy, the organ or tissue's ischemic.

On the other hand, the invention provides through treating the kinase mediated disease or the method for the patient's condition to formula (I) compound of experimenter's administering therapeutic effective dose or its pharmaceutically acceptable salt and with second kind of treatment combination of agents.

In the said method that uses The compounds of this invention, formula (I) compound or pharmaceutically acceptable salt are bestowed the system that comprises cell or tissue.In certain embodiments, use formula (I) compound, its pharmaceutically acceptable salt, its pharmaceutical composition or medicament to human or animal experimenter.

Embodiment

The invention provides one group of Pyrrolopyrimidine derivatives and pharmaceutically acceptable salt thereof; Be used to suppress one or more protein kinases; And be used to treat by said protein kinase mediated disease and obstacle disease; For example cell proliferation disorders and obstacle disease, for example cancer, autoimmune disease, infection, cardiovascular disease, and nerve degenerative diseases and obstacle disease (for example Alzheimer disease).The present invention also provides synthetic and has used the method for said Pyrrolopyrimidine derivatives.The present invention also provides pharmaceutical preparation, and this pharmaceutical preparation comprises at least a The compounds of this invention and pharmaceutically acceptable carrier, thinner or excipient.The present invention also provides the useful as intermediates that during synthetic pyrrolopyrimidine derivative compound, is produced.

The invention provides mixture or its pharmaceutically acceptable salt of a kind of formula I compound or its single stereoisomer or isomer,

Formula I

X is CH or N.

R ¹Be selected from H, halogen, CN, C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) alkyl.For example, R ¹Can be H, F, Cl, Br, CF ₃, or CH ₃R ¹C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) alkyl can be randomly through one or more suitable substituting groups replacements, wherein suitable substituting group is halogen, amino, hydroxyl, alkoxyl or haloalkyl for example.

R ²Be aryl, cycloalkyl, aryl alkyl or heterocyclic radical.R ²Aryl, cycloalkyl, aryl alkyl or heterocyclic radical optional and independently at one or more carbon atoms place through 1-4 R ⁵Or R ^5aGroup replace and at one or more nitrogen-atoms place through 1-4 R ⁶Or R ^6aGroup replaces.R ²Can be and contain one or more heteroatomic aryl, aryl alkyl or heterocyclic radical, wherein hetero atom is selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.Said R ²Heteroaryl, heteroaryl alkyl or heterocyclic radical contain one or more nitrogen heteroatoms, wherein nitrogen heteroatom is optional and independently through 1-4 R ⁶Or R ^6aGroup replaces.

R ²Aryl generally comprise (but being not limited to): the heteroatomic 5-6 of 0-3 unit monocyclic aryl is contained in (1), and wherein hetero atom is independently selected from nitrogen, oxygen or sulphur; (2) contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; (3) contain the aryl bicyclic of the heteroatomic 8-10 of 0-5 unit fractional saturation, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Or the aryl bicyclic of the 8-10 unit fractional saturation of formamide or sulfonamide is contained in (4).R ²The limiting examples of aryl comprises: phenyl, 3-chlorphenyl, 2; 6-dibromo phenyl, pyrimidine radicals, pyridine radicals, 3-picolyl, benzothienyl, 2; 4; 6-tribromo phenyl, 4-ethyl benzothienyl, furyl, benzofuranyl, indyl, indazolyl, dihydrobenzo bioxin base, dihydro indenyl, 3,4-diethyl furyl, naphthyl, tetralyl, quinolyl, 4,7-dichloro naphthyl, pyrroles, pyrazoles, imidazoles, thiazole etc.R ²Aryl can be randomly through replacing.

Particularly, R ²Can be and contain 0-3 the first monocyclic aryl of heteroatomic 5-6, wherein hetero atom is independently selected from nitrogen, oxygen or sulphur.For example, R ²5-6 unit monocyclic aryl be phenyl, this phenyl is optional and be selected from following group through 1,2 or 3 independently and replace: methyl, ethyl, isopropyl, methoxyl group, 2-hydroxyl-oxethyl, CF ₃, OC ₆H ₅, OCH ₂C ₆H ₅, OCH ₂CH ₂NR ¹¹R ¹², OCH ₂CH ₂NR ⁷R ⁷, OCH ₂C (O) NR ¹¹R ¹², OCH ₂C (O) NR ⁷R ⁷, OSO ₂CH ₃, SO ₂CH ₃, SO ₂NHCH ₃, or NR ¹¹R ¹²Hydroxyl-oxethyl is OCH ₂CH ₂OH.In brief, OCH ₂CH ₂NR ¹¹R ¹², OCH ₂C (O) NR ¹¹R ¹², or NR ¹¹R ¹²R ¹¹R ¹²Nitrogen-atoms with their institute's key knots can form: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot, for example, pyrrolidinyl or piperidyl; Or (ii) except that R ¹¹And R ¹²Also contain 1-3 heteroatomic 5-8 first saturated or fractional saturation ring, for example morpholinyl, piperazinyl or high piperazinyl beyond the nitrogen-atoms of institute's key knot.To R ¹¹R ¹²Elaboration will do hereinafter further in detail to discuss.

R ²Can be and contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone.For example; The first aryl bicyclic of said 8-10 can be selected from indyl, indazolyl, benzothienyl, benzothiazolyl, benzofuranyl, naphthyl or quinolyl; And it is optional and be selected from following group replacement at commutable carbon atom or 1,2 or 3 at nitrogen-atoms place independently: alkyl, aryl, heteroaryl, alkoxyl, halogen, haloalkyl, cycloalkyl or sulfone, for example CF ₃, OCF ₃, C (O) C ₆H ₅Or S (O) ₂CH ₃Wherein alkyl, aryl or heteroaryl randomly replace through hydroxyl, amino or sulfone.

R ²Can be the bicyclic groups of the 8-10 unit fractional saturation that contains phenyl ring, wherein phenyl ring with contain 0-5 heteroatomic non-aromatic carbocyclic ring or heterocyclic fused, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone.For example, the bicyclic groups of 8-10 unit fractional saturation is dihydro indenyl, tetralyl or dihydrobenzo bioxin base, optional and independently at commutable carbon atom place 1,2 or 3 be selected from alkyl, aryl, heteroaryl, alkoxyl, halogen, CF ₃, OCF ₃, or SO ₂CH ₃Group replace.

R ³Can be H, halogen, CN or R ⁷For example, R ³Be selected from H, C ₁-C ₆Alkyl, cycloalkyl or aryl.Preferably, R ³Be selected from H, cyclopropyl, isopropyl, furyl, methyl, ethyl, CF ₃, or phenyl.Methyl, ethyl or phenyl can be chosen wantonly and independently through one or more halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R of being selected from ⁹, or R ¹⁰Group replace.

Each R ⁵Be independently selected from halogen, CF ₃, SR ⁷, OR ⁷, OC (O) R ⁷, O (CH ₂) _nNR ⁷R ⁷, O (CH ₂) _nNR ¹¹R ¹², O (CH ₂) _nR ⁷, O (CH ₂) _nC (O) NR ¹¹R ¹², O (CH ₂) _nC (O) NR ⁷R ⁷, NR ⁷R ⁷, NR ⁷R ⁸, NHC (O) NH ₂, C (O) OR ⁷, NO ₂, CN, C (O) R ⁷, OSO ₂CH ₃, S (O) _nR ⁷, S (O) _nNR ⁷R ⁷, NR ⁷C (O) NR ⁷R ⁷, NR ⁷C (O) R ⁷, NR ⁷C (O) OR ⁷, NR ⁷S (O) _nR ⁷, or NR ¹¹R ¹²Each n is 1 or 2 all independently.

Each R ^5aBe independently selected from amino, halogen, hydroxyl, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, alkoxyl, haloalkyl, aryl, heteroaryl or heterocyclic radical.R wherein ^5aC ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, alkoxyl, haloalkyl, aryl, heteroaryl or heterocyclic radical are optional and be selected from halogen, hydroxyl, alkyl, R through 1 to 3 independently ⁹, or R ¹⁰Group replace.

Each R ^6aBe hydroxyl, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₀Cycloalkenyl group, haloalkyl.Each R ^6aGroup is optional and be selected from hydroxyl, aryl, alkyl, halogen, R through 1-3 independently ⁹, or R ¹⁰Group replace.

Each R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, aryl (C ₁-C ₄) alkyl, haloalkyl, heteroaryl or heterocyclic radical.C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, aryl (C ₁-C ₄) alkyl, haloalkyl, heteroaryl or heterocyclic radical is optional and be selected from aryl, cycloalkyl, heteroaryl, heterocyclic radical, alkyl, halogen, amino, hydroxyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.

Each R ⁸Be C (O) R independently ⁷, C (O) OR ⁷, C (O) NR ⁷R ⁷Or S (O) _nR ⁷N is 1 or 2.

Each R ⁹Be CF independently ₃, SR ⁷, OR ⁷, NR ⁷R ⁷, NR ¹¹R ¹², C (O) NR ⁷R ⁷, C (O) NR ¹¹R ¹², S (O) _nNR ⁷R ⁷, or S (O) _nR ⁷, wherein each n is 1 or 2 all independently.Each n is 1 or 2 all independently.

Each R ¹⁰Be all C (O) O (C ₁-C ₆) alkyl or halo (C ₁-C ₄) alkyl.

R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot; Saturated or the fractional saturation ring of said 3-8 unit includes, but is not limited to azelidinyl, pyrrolidinyl or piperidyl, and optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace; (ii) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot, wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide; And the heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring includes, but is not limited to morpholinyl, thiomorpholine base, piperazinyl or high piperazinyl, and optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace; (iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace; (iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide; Or, (v) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

R ⁴Be selected from (CH ₂) _nOH, (CH ₂) _nNR ¹¹R ¹², C (O) NHR ⁷, C (O) NR ¹¹R ¹², C (O) OR ⁷, C (O) R ⁷, C (O) NR ⁷R ⁷, C (O) NR ⁷R ⁸, (CH ₂) _nNR ⁷R ⁷, (CH ₂) _nNR ⁷R ⁸, (CH ₂) _nCN, (CH ₂) _nSR ⁷, (CH ₂) _nS (O) _nR ⁷, or (CH ₂) _nS (O) _nNR ⁷R ⁷Each n is 1 or 2 all independently.

Work as R ⁴Be C (O) OR ⁷The time, C (O) OR ⁷R ⁷Be H, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl or heterocyclic radical.C wherein ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl or heterocyclic radical are optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.Work as R ⁴Be C (O) OR ⁷The time, R ⁷Be preferably methyl, ethyl or propyl group, and optional and independently through one or more halogen, hydroxyl, amino, C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

Work as R ⁴Be C (O) R ⁷The time, C (O) R ⁷R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl or heterocyclic radical.By R ⁷Represented group is optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-3 independently ⁹, or R ¹⁰Group replace.For example, R ⁷Can be selected from H or C ₁-C ₁₀Alkyl, and R ⁷Group can be chosen wantonly and be selected from halogen, hydroxyl, amino, C through 1-4 independently ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

Work as R ⁴Be C (O) NHR ⁷The time, C (O) NHR ⁷R ⁷Be selected from H, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical.C wherein ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical are optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.In one embodiment, R ⁷Be phenyl, and can choose wantonly and be selected from methyl, ethyl, methoxyl group, CF through 1,2 or 3 independently ₃, OC (O) R ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, C (O) NHR ⁷, or SO ₂CH ₃Group replace.R ⁷Can be C ₁-C ₁₀Alkyl, and said C ₁-C ₁₀Alkyl group is optional and be selected from amino, halogen, hydroxyl, phenyl, C through 1-3 independently ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

Work as R ⁴Be C (O) NR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot, wherein said 3-8 unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace; (ii) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace; (iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein saidly do not contain heteroatomic 9-10 unit's ring filling or fractional saturation two rings randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace; Or, (iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.

Work as R ⁴Be C (O) NR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot.Said except that the nitrogen-atoms of institute key knot, do not contain heteroatomic 3-8 unit saturated or the fractional saturation ring optional and independently at one or more substitutable carbon atoms place through the individual R that is selected from of 1-4 ⁵Or R ^5aGroup replace.For example; The said saturated or fractional saturation ring of heteroatomic 3-8 unit that except that the nitrogen-atoms of institute key knot, do not contain can be azelidinyl, pyrrolidinyl or piperidyl, wherein azelidinyl, pyrrolidinyl or piperidyl optional and independently at substitutable carbon atom place through individual hydroxyl, the CH of being selected from of 1-4 ₂OH, CH ₂CH ₂OH, NH ₂, NHR ⁷, NHCOR ⁷, NHC (O) NHR ⁷, or NR ⁷R ⁷Group replace.

Work as R ⁴Be C (O) NR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot.Said 5-8 unit 1-3 hetero atom saturated or the fractional saturation ring is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide.The heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring can be chosen wantonly and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.Said hetero atom can be one or more nitrogen-atoms, and said one or more nitrogen-atoms can be chosen wantonly and independently through 1-4 R ⁶Or R ^6aGroup replaces.

Work as R ⁴Be C (O) NR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot.Said except that the nitrogen-atoms of institute key knot, do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit randomly at one or more substitutable carbon atoms place through the individual R that is independently selected from of 1-4 ⁵Or R ^5aGroup replace.Said saturated or fractional saturation two rings of heteroatomic 9-10 unit that except that the nitrogen-atoms of institute key knot, do not contain can two encircle and contain aryl at this.

Work as R ⁴Be C (O) NR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein 1-5 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.Saturated or fractional saturation two rings of the heteroatomic 9-10 of the said 1-5 of containing unit can be chosen wantonly and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.Wherein 1-5 hetero atom can be one or more nitrogen-atoms, and said one or more nitrogen-atoms can be chosen wantonly and independently through 1-4 R ⁶Or R ^6aGroup replaces.Saturated or fractional saturation two rings of the heteroatomic 9-10 of the said 1-5 of containing unit can contain aryl at this bicyclic groups.

Work as R ⁴Be (CH ₂) _nNR ⁷R ⁷The time, (CH ₂) _nNR ⁷R ⁷R ⁷Be independently selected from H, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical.C wherein ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical are optional and be selected from halogen, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.For example, R ⁷Can be H or C independently ₁-C ₁₀Alkyl, and R ⁷Optional and replace through 1-4 group that is selected from hydroxyl, amino, aryl, alkyl or halogen independently.In one embodiment, C ₁-C ₁₀Alkyl randomly replaces through phenyl, and wherein phenyl can be chosen wantonly and independently through one or more alkyl, halogen, amino, hydroxyl, alkoxyl or CF ₃Replace.

Work as R ⁴Be (CH ₂) _nNR ¹¹R ¹²The time, R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms: (i) remove R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot, wherein said 3-8 unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace; (ii) remove R ¹¹And R ¹²Also contain beyond the nitrogen-atoms of institute key knot 1-3 heteroatomic 5-8 unit saturated or the fractional saturation ring; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace; (iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace; (iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide; Or, (v) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; Wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot.Said except that the nitrogen-atoms of institute key knot, do not contain heteroatomic 3-8 unit saturated or the fractional saturation ring optional and independently at one or more substitutable carbon atoms place through the individual R that is selected from of 1-4 ⁵Or R ^5aGroup replace.The said saturated or fractional saturation ring of heteroatomic 3-8 unit that except that the nitrogen of institute key knot, do not contain can be at one or more substitutable carbon atoms place through choosing substituted 4,5 or 6 yuan of saturated rings wantonly.Preferably, the first ring of said 3-8 is azelidinyl, pyrrolidinyl or piperidyl, and wherein azelidinyl, pyrrolidinyl or piperidyl are chosen wantonly and be selected from hydroxyl, halogen, OC (O) R at one or more substitutable carbon atoms place through 1-2 independently ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, or C (O) NHR ⁷Group replace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot, wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide.The heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.For example, the heteroatomic 5-8 of the said 1-3 of containing unit is saturated or the fractional saturation ring is to contain 1 heteroatomic 6 yuan or 7 yuan of saturated rings.Said hetero atom can be nitrogen, and wherein nitrogen is randomly through C ₁-C ₁₀Alkyl, hydroxyl C ₂-C ₁₀Alkyl or C (O) NHR ⁷Replace.Perhaps, said hetero atom can be oxygen.In one embodiment, oxygen and R ¹¹, R ¹²And the nitrogen-atoms of their institute's key knots can form morpholinyl.Therefore, the saturated or fractional saturation ring of the heteroatomic 5-8 of the said 1-3 of containing unit can be morpholinyl, thiomorpholine base, piperazinyl or high piperazinyl.Piperazinyl or high piperazinyl optional and independently at the nitrogen-atoms place through one or more hydroxyl, C of being selected from ₁-C ₁₀Alkyl, CH ₂CH ₂OH, C (O) R ⁷, C (O) NHR ⁷, SO ₂R ⁷, SO ₂NHR ⁷, or C (O) OR ⁷Group replace.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot.It is said that except that the nitrogen-atoms of institute key knot, not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit are tetrahydroisoquinolines, wherein tetrahydroisoquinoline randomly at one or more substitutable carbon atoms place through the individual R that is independently selected from of 1-4 ⁵Or R ^5aGroup replace.Said two rings also can contain aryl at this ring.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein 1-5 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.Saturated or fractional saturation two rings of the heteroatomic 9-10 of the said 1-5 of containing unit can be chosen wantonly and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.Said two rings also can contain aryl at this ring.

In one embodiment, R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots can form except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot, wherein 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide.The heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

When independent use of term " alkyl " or conduct are used than the part of macoradical (for example " aryl alkyl " or " cycloalkyl ") part; Be meant the straight or branched alkyl that contains 1-15 carbon atom (except as otherwise noted), and comprise (for example) methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl etc.Alkyl can be without replacing or replacing through one or more suitable substituting groups.

Term " cycloalkyl " is meant monocycle or polycyclic hydrocarbon cyclic group, and comprises (for example) cyclopropyl, suberyl, ring octyl group, ring decyl, cyclobutyl, golden steel alkyl, norpinane base, decahydro naphthyl (decalinyl), norcamphane base (norbornyl), cyclohexyl, cyclopenta etc.Cycloalkyl can be without replacing or replacing through one or more suitable substituting groups.

Term " is mixed " and is meant at least one carbon atom with at least one hetero atom (for example N, S and O) alternate collar system.

Term " Heterocyclylalkyl " means non-aromatic monocycle or many rings, and it comprises carbon and hydrogen atom and at least one hetero atom (being preferably 1-4 hetero atom that is selected from N, O, S, sulfone or sulfoxide).Heterocyclylalkyl can contain one or more carbon-to-carbon double bonds or the two keys of carbon-hetero atom at cyclic group, and condition is that this cyclic group is not given aromaticity because of the appearance of this pair key.The instance of Heterocyclylalkyl comprises azelidinyl, aziridinyl, pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl, morpholinyl, thiomorpholine base, tetrahydrofuran base, tetrahydrochysene thio-furan base, THP trtrahydropyranyl, pyranose etc.Heterocyclylalkyl can be without replacing or replacing through one or more suitable substituting groups.

Term used herein " halogen " comprises fluorine, chlorine, bromine and iodine.

Term used herein " thiazolinyl " is meant straight chain and the branched hydrocarbyl that contains 2-6 carbon atom and two keys, comprises vinyl, 3-butene-1-Ji, 2-vinyl butyl, 3-hexene-1-base etc.Thiazolinyl can be without replacing or replacing through one or more suitable substituting groups.

Term used herein " alkynyl " is meant straight chain and the branched hydrocarbyl that contains a 2-6 carbon atom and a triple bond, comprises acetenyl, 3-butine-1-base, propinyl, 2-butine-1-base, 3-pentyne-1-base etc.Alkynyl can be without replacing or replacing through one or more suitable substituting groups.

Term used herein " alkoxyl " is meant the alkyl of above-mentioned logical peroxide bridge knot, and the example comprises methoxyl group, ethyoxyl, isopropoxy, tert-butoxy etc.In addition, alkoxyl also refers to polyethers, for example-and O-(CH ₂) ₂-O-CH ₃Deng.Alkoxyl can be without replacing or replacing through one or more suitable substituting groups.

Term used herein " aryl " is meant without replacing or through substituted aromatic series monocycle or many cyclic groups, comprising (for example) phenyl and naphthyl.Term " aryl " also comprises and non-aromatic carbocyclic ring or heterocyclic fused phenyl ring.Term " aryl " can exchange with " aryl rings ", " aromatic group " and " aromatic ring " and use.Heteroaryl contains 4-14 atom, and wherein 1-9 atom is independently selected from the group of being made up of O, S and N.Heteroaryl contains 1-3 hetero atom in 5-8 unit aromatic group.Aryl or heteroaryl can be monocycle-or two cyclic aromatic series groups.Typical aryl and heteroaryl comprise (for example) phenyl, quinolyl, indazolyl, indyl, dihydrobenzo bioxin base, 3-chlorphenyl, 2; 6-dibromo phenyl, pyridine radicals, pyrimidine radicals, 3-picolyl, benzothienyl, 2; 4; 6-tribromo phenyl, 4-ethyl benzothienyl, furyl, 3,4-diethyl furyl, naphthyl, 4,7-dichloro naphthyl, pyrroles, pyrazoles, imidazoles, thiazole etc.Aryl or heteroaryl can be without replacing or replacing through one or more suitable substituting groups.

Term used herein " haloalkyl " is meant any alkyl that one or more hydrogen atoms are substituted by halogen atom.The instance of haloalkyl comprises-CF ₃,-CFH ₂,-CF ₂H etc.

Term used herein " aryl alkyl " is meant any alkyl that one or more hydrogen atoms are substituted by aryl.The instance of aryl alkyl comprises benzyl (C ₆H ₅CH ₂-) etc.

Term used herein " hydroxyl (hydroxyl or hydroxy) " is meant-OH.

Term used herein " amino " is meant-NH ₂

Term used herein " hydroxy alkyl " is meant any hydroxy derivatives of alkyl.Term " hydroxy alkyl " comprises any alkyl that one or more hydrogen atom quilt-OH groups substitute.

Term used herein " kinases panel (kinase panel) " is meant that one group of kinases lists; Include, but is not limited to ABL1 (E255K)-phosphorylation, ABL1 (T315I)-phosphorylation, ABL1-phosphorylation, ACVR1B, ADCK3, AKT1, AKT2, ALK, AURKA, AURKB, AXL, BMPR2, BRAF, BRAF (V600E), BTK, CDK11, CDK2, CDK3, CDK7, CDK9, CHEK1, CSF1R, CSNK1D, CSNK1G2, DCAMKL1, DYRK1B, EGFR, EGFR (L858R), EPHA2, ERBB2, ERBB4, ERK1, FAK, FGFR2, FGFR3, FLT1, FLT3, FLT4, GSK3B, IGF1R, IKK-α, IKK-β, INSR, JAK2 (JH1 domain-catalysis), JAK3 (JH1 domain-catalysis), JNK1, JNK2, JNK3, KIT, KIT (D816V), KIT (V559D, T670I), LKB1, LRRK2, LRRK2 (G2019S), MAP3K4, MAPKAPK2, MARK3, MEK1, MEK2, MET, MKNK1, MKNK2, MLK1, MTOR, p38-α, p38-β, PAK1, PAK2, PAK4, PCTK1, PDGFRA, PDGFRB, PDPK1, PIK3C2B, PIK3CA, PIK3CG, PIM1, PIM2, PIM3, PKAC-α, PLK1, PLK3, PLK4, PRKCE, PYK2, RAF1, RET, RIOK2, ROCK2, RSK2, SNARK, SRC, SRPK3, SYK, TAK1, TGFBR1, TIE2, TRKA, TSSK1B, TYK2 (JH1 domain-catalysis), ULK2, VEGFR2, YANK3 and ZAP70.Can on market, buy and comprise kinase whose kinases check panel (panel) described herein, be used for the selectivity of inhibitors of kinases is suppressed to carry out the analysis of biochemistry spectral pattern.

Term used herein " dept. of dermatology's obstacle disease (dermatological disorder) " is meant skin barrier property disease.Said dept. of dermatology obstacle disease includes, but is not limited to the proliferative or the struvite obstacle disease of skin, and for example atopic dermatitis, epidermolysis obstacle disease, collagenosis, contact dermatitis, eczema, Kawasaki disease (Kawasaki Disease), brandy nose, Xue's lattice connect Cotard (Sjogren-Larsso Syndrome) and nettle rash.

Term used herein " neurogenic disease " or " nervous system disorders property disease " are meant the patient's condition that changes brain, spinal cord or peripheral nervous system structure or function, include, but is not limited to Alzheimer disease, encephaledema, cerebral ischemia, multiple sclerosis, neuropathy, Parkinson's, the disease (cognition dysfunction after comprising operation and spinal cord or brain-stem injury) that behind blunt wound or operation wound, occurs and neurological obstacle disease (for example degenerative disc disease and sciatica).Abbreviation " CNS " is meant central nervous system (brain and spinal cord).

Term used herein " respiratory disorder " is meant that influence relates to the disease of respiratory apparatus (for example nose, throat, larynx, tracheae, bronchi and lung).Respiratory disorder includes, but is not limited to asthma; Adult respiratory distress syndrome (ARDS) and allergia (external) asthma; Anallergic (inherence) asthma; Acute serious asthma; Chronic asthma; Clinical asthma; Night asthma; The asthma that allergen is induced; ASA; The asthma of exercise induced; Deng the carbonic acid gas hyperventilation; The asthma that Childhood begins; The asthma that begins behind the adult; Cough variant asthma; Occupational asthma; Hormonal resistance property asthma; Seasonal asthma; The pollinosis; Long-term allergic rhinitis; COPD (comprising chronic bronchitis or pulmonary emphysema); Pulmonary hypertension; Between matter pulmonary fibrosis and/or tracheitis; And cystic fibrosis; And anoxic.

Term used herein " cancer " is the misgrowth of phalangeal cell, and said growth often phalangeal cell is bred with uncontrollable mode and shifted in some cases.The type of cancer comprises (but being not limited to) solid tumor; For example bladder, intestines, brain, mammary gland, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas; Or the tumour of other endocrine organ (thyroid gland), prostate, skin (melanoma), or neoplastic hematologic disorder (for example leukemia).

Term used herein " inflammation obstacle disease " is meant the disease or the patient's condition with one or more characteristic in the following symptom: pain (bitterly; Cause with nerve stimulation by producing noxious material), (heat of generating heat; Cause by blood vessel dilatation), the rubescent (redness of skin; CBF by blood vessel dilatation and increase causes), swelling (lump is caused by the excessive inflow or the restricted outflow of fluid), and afunction, these symptoms can be partially or completely, interim or lasting.Inflammation presents various ways, include, but is not limited to appear following in the inflammation of one or more forms: acute, adhesivity, atrophic, Catarrhal (catarrhal), chronic, cirrhosis property, diffusibility, dispersivity, exudative, fiber disposition, fibrillatable, locality, granulomatous, (hyperplastic), hypertrophy property that quantity property is loose, a matter property, metastatic, gangrenosum acne, occlusive, substance, adaptability (plastic), hyperplasia property (productive), proliferative, pseudomembrane property, suppurative, hardening, pulp fibers albumen property, serosity, simple, specificity, subacute, urge purulence, toxic, traumatic and/or ulcer property.The inflammation obstacle disease further includes, but is not limited to influence the disease (panarteritis, interim arteritis) of blood vessel, the disease that influences the joint (crystallinity, bone, chronic eczema property, reactivity, rheumatoid, Lay Te Shi (Reiter ' s) arthritis), influences GI disease, cutaneous disease (dermatitis) or influences the disease (systemic loupus erythematosus) of many organs and tissue.

Term used herein " angiocardiopathy " is meant to be influenced heart or blood vessel or influences heart and the disease of blood vessel, includes, but is not limited to: reperfusion injury, endotoxin induction or operation or traumatic shock, hypertension, valvular heart disease, heart failure, abnormal blood pressure, vessel retraction, aberrant angiogenesis or inflammation around atherosclerotic, arrhythmia, pharyngalgia, myocardial ischemia, miocardial infarction, heart or vascular knurl, vasculitis, apoplexy, limbs or the organ or tissue behind obstructive arteriopathy, the organ or tissue's ischemic.

Term used herein " osteopathy " means the disease or the patient's condition of bone, and including, but is not limited to unsuitable bone reconstruction, bone loss or bone amount increases disease, osteopenia disease, malacosteon, osteofibrosis, osteoporosis and Paget disease (Paget ' s disease).

Term used herein " inhibitor " is meant and suppresses one or more kinase whose compounds described herein.For example, term " SYK inhibitor " is meant the compound that suppresses the SYK acceptor or reduce its Role in Plant Signal Transduction.

Term used herein " pharmaceutically acceptable " is meant that a kind of material such as for example carrier or thinner etc. can not eliminate the biologically active or the characteristic of compound described herein.Use this material to individuality, can not cause unwanted biological effect or with any component interaction in harmful mode and the composition that is comprised.

Term used herein " pharmaceutically acceptable salt " is meant a kind of compound formulation, and said preparation can not produce obvious stimulation and can not eliminate the biologically active and the characteristic of compound described herein to the organism of institute's administration.

Term used herein " pharmaceutical composition " is meant the mixture of a kind of compound described herein and other chemical constituent, and wherein said other chemical constituent is carrier, stabilizing agent, thinner, dispersant, suspending agent, thickener and/or excipient for example.

Term used herein " prodrug " is meant a kind of medicament that is converted into parent drug in vivo.

Term used herein " protein kinase mediated disease " or " by unsuitable protein kinase activity disorder mediated property disease or the disease or the patient's condition " are meant by protein kinase mediated or any morbid state of regulating described herein.These morbid states include, but is not limited to: asthma; COPD (COPD); Adult respiratory distress syndrome (ARDS) (ARDS); Ulcerative colitis; Crohn's disease; Bronchitis; Dermatitis; Allergic rhinitis; Psoriasis; Chorionitis; Nettle rash; The epidermolysis obstacle disease; Collagenosis; Contact dermatitis; Kawasaki disease; Brandy nose; Xue's lattice connect Cotard; Rheumatoid arthritis; Multiple sclerosis; IBD; HIV; Lupus; Lymphoma; Osteosarcoma; Melanoma; Breast cancer; Kidney; Prostate cancer; Colorectal cancer; Thyroid cancer; Oophoroma; Cancer of pancreas; Neural cancer; Lung cancer; The cancer of the uterus; Human primary gastrointestinal cancers; Alzheimer disease; Parkinson's; Osteoporosis; Osteopenia disease; Malacosteon; Osteofibrosis; Paget disease; Diabetes; The blood vessel hyperplasia obstacle disease; Illness in eye; Cardiovascular disease; Restenosis; Fibrillatable; Atherosclerotic; Arrhythmia; Pharyngalgia; Myocardial ischemia; Miocardial infarction; Heart or vascular knurl; Vasculitis; Apoplexy; Obstructive arteriopathy on every side; Reperfusion injury behind organ or tissue's ischemic; Endotoxin induction or operation or traumatic shock; Hypertension; Valvular heart disease; In heart failure; Abnormal blood pressure; Vessel retraction; Aberrant angiogenesis; Graft rejection; Sick with the infection that comprises virus and fungal infection.

Term used herein " kinase mediated disease " or " kinase mediated disease " or " by unsuitable kinase activity disorder mediated property disease or the disease or the patient's condition " are meant any morbid state by mediation of kinases mechanism or adjusting.For example, " disease of SYK-mediation " is meant any morbid state by mediation of SYK mechanism or adjusting.These SYK-disease states mediated include, but is not limited to diseases associated with inflammation, respiratory disorder and autoimmune disease, for example relevant disease and the lupus of (only as an example) asthma, COPD (COPD), adult respiratory distress syndrome (ARDS) (ARDs), ulcerative colitis, Crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, chorionitis, nettle rash, rheumatoid arthritis, multiple sclerosis, cancer, HIV.

Term used herein " disease of PYK2-mediation " or " by the active disorder mediated property disease of unsuitable PYK2 or the disease or the patient's condition " are meant any morbid state by mediation of PYK2 kinases mechanism or adjusting.These morbid states include, but is not limited to osteoporosis, arthritis, myelomatosis, low osmotic pressure, sarcoma, BC, glioma, erythroleukemia and cancer.

Term used herein " disease of ZAP70-mediation " or " by the active disorder mediated property disease of unsuitable ZAP70 or the disease or the patient's condition " are meant any morbid state by mediation of ZAP70 kinases mechanism or adjusting.The selectivity shortage that these morbid states include, but is not limited to by the positive T-cell of CD8-is the immune deficiency disorder that characterizes.

Term used herein " disease of FAK-mediation " or " by the active disorder mediated property disease of unsuitable FAK or the disease or the patient's condition " are meant any morbid state by mediation of FAK kinases mechanism or adjusting.These morbid states include, but is not limited to cancer, macular degeneration or increase the relevant patient's condition with the angiogenesis horizontal abnormality.

Term used herein " disease of PIM1-mediation " or " by the active disorder mediated property disease of unsuitable PIM1 or the disease or the patient's condition " are meant any morbid state by mediation of PIM1 kinases mechanism or adjusting.These morbid states include, but is not limited to cancer, myeloproliferative disease, autoimmune disease, allergic reaction and organ-graft refection's syndrome.

Term used herein " disease of FLT3-mediation " or " by the active disorder mediated property disease of unsuitable FLT3 or the disease or the patient's condition " are meant any morbid state by mediation of FLT3 kinases mechanism or adjusting.These morbid states include, but is not limited to comprise the leukemia of acute myelogenous leukemia or increase the relevant patient's condition with FLT3 kinases horizontal abnormality.

Term used herein " disease of RET-mediation " or " by the active disorder mediated property disease of unsuitable RET or the disease or the patient's condition " are meant any morbid state by mediation of RET kinases mechanism or adjusting.These morbid states include, but is not limited to thyroid cancer, increase the relevant patient's condition with RET kinases horizontal abnormality.

Term used herein " disease of JAK2-mediation " or " by the active disorder mediated property disease of unsuitable JAK2 or the disease or the patient's condition " are meant any morbid state by mediation of JAK2 kinases mechanism or adjusting.These morbid states include, but is not limited to polycythemia vera, primary thrombocytosis, other myeloproliferative disorder property cancer (myeloproliferative disorders cancer) or increase the relevant patient's condition with JAK2 kinases horizontal abnormality.

Term used herein " disease of LRRK2-mediation " or " by the active disorder mediated property disease of unsuitable LRRK2 or the disease or the patient's condition " are meant any morbid state by mediation of LRRK2 kinases mechanism or adjusting.These morbid states include, but is not limited to Parkinson's, other nerve degenerative diseases or increase the relevant patient's condition with the angiogenesis horizontal abnormality.

Term used herein " treatment effective dose " is meant any amount of the compound with following effect: compare with the corresponding experimenter who does not accept this amount; Obtain disease, obstacle disease or side effect are had improved treatment, healing, prevention or improve effect, or reduce the speed that disease or obstacle disease further develop.This term also comprises the amount of effective raising normal physiological function in its scope.

Term used herein " treatment (treat, treating or treatment) " be meant alleviate, alleviate or improve disease or patient's condition symptom, prevent other symptom, metabolism reason that improvement or prevention symptom are potential, suppress disease or the patient's condition, prevention disease or patient's condition development, remove the disease or the patient's condition, the disease that disappears or the patient's condition, method that the patient's condition that releasing is caused by the disease or the patient's condition or preventative and/or therapeutic stop disease or patient's condition symptom.

Term used herein " solvate " is meant a kind of by solute and the variable compound of the formed stoichiometry of solvent; In the present invention, said solute is formula (I) compound or its pharmaceutically acceptable salt.Can not disturb the biologically active of solute for the said solvent of the object of the invention.The limiting examples of suitable solvent comprises water, acetone, methyl alcohol, ethanol and acetate.Preferably, employed solvent is pharmaceutically acceptable solvent.The limiting examples of suitable pharmaceutically acceptable solvent comprises water, ethanol and acetate.

Term used herein " experimenter " or " patient " are contained mammal and nonmammalian.Mammiferous instance includes, but is not limited to people, chimpanzee, ape and monkey, ox, horse, sheep, goat, pig, rabbit, dog, cat, rat, mouse, cavy etc.The instance of nonmammalian includes, but is not limited to bird, fish etc.

" administration " of term subject compound used herein or " using " are meant that the experimenter for there being treatment to need provides compound of the present invention.

Term used herein " carrier " is meant and helps to make compound described herein to get into chemical compound or reagent in the cell or tissue.

With regard to preparation used herein, composition or composition, the general health that term used herein " acceptable " means the experimenter who is receiving treatment does not have lasting adverse effect.

Term used herein " thinner " is meant the chemical compound that before sending, is used for diluting compound described herein.Thinner also can be used to stablize compound described herein.

Term used herein " effective dose " or " treatment effective dose " are meant enough amounts of giving drug compound described herein, and it alleviates the disease of treating or one or more symptoms of the patient's condition to a certain extent.

1, human protein kinase

Protein kinase plays an important role in regulating various kinds of cell process and cellular function retentive control.Protein kinase catalysis is also regulated the phosphorylation process, thereby response various kinds of cell external signal is covalently bound on albumen or lipid target spot with phosphate groups.The instance of this stimulation comprises that hormone, neurotransmitter, growth and differentiation factor, cell cycle events, environmental stress and nutrition stress.Extracellular stimulus can influence activation, contraction of muscle, glucose metabolism, synthetic control one or more cellular response relevant with regulation of Cell Cycle of albumen with cell growth, migration, differentiation, hormone secretion, transcription factor.

Through the method for at least a kinase activity on kinases panel and the inhibition panel, The compounds of this invention is screened.Kinase whose instance include, but is not limited to SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2 kinases and mutant forms thereof.Like this, The compounds of this invention and composition can be used for treating wherein disease or obstacle disease and/or the disease relevant with these kinases or the symptom of obstacle disease that causes pathological change owing to these kinases.These diseases or obstacle disease include, but is not limited to cancer of pancreas; Papillary thyroid carcinoma; Oophoroma; People's adenoid cystic carcinoma; Non-small cell lung cancer; Secreted breast cancer; Congenital fibrosarcoma; CMN; Acute myelogenous leukemia; Psoriasis; Shift; The pain relevant with cancer; And nerve-cell tumor; Autoimmune disease; Diseases associated with inflammation; Osteopathy; Metabolic disease; Neuropathy and nerve degenerative diseases; Cancer; Cardiovascular disease; Respiratory disorder; Allergy and asthma; Alzheimer disease; With with the hormone diseases associated; Optimum and malignant proliferation obstacle disease; By the caused disease of unsuitable immune system activation; With activate caused disease by unsuitable nervous system; Allograft rejection; Graft versus host disease; DRP; The CNV property disease that the macular degeneration of being correlated with by the age causes; Psoriasis; Arthritis; Osteoarthritis; Rheumatoid arthritis; Arthritic synovial membrane pannus is invaded; Multiple sclerosis; Myasthenia gravis; Diabetes; Diabetic angiopathy; The PVR of premature labor; Infantile hemangioma; Non-small cell lung cancer; Bladder and head and neck cancer; Prostate cancer; Breast cancer; Oophoroma; Stomach and cancer of pancreas; Psoriasis; Fibrotic disease; Atherosclerotic; Restenosis; Autoimmune disease; Anaphylaxis; Respiratory disorder; Asthma; Graft rejection; Inflammation; DVT; The retinal vessel hyperplasia; IBD; Crohn's disease; Ulcerative colitis; Osteopathy; Transplant or marrow graft rejection; Lupus; Chronic pancreatitis; Cachexia; Infectious shock; Fibroplasia property and differentiation dermatoses or obstacle disease; Central nervous system disease; Nerve degenerative diseases; Alzheimer disease; Parkinson's; The obstacle disease relevant or the patient's condition with nervous lesion; With the aixs cylinder retrogression pathological changes after brain or the spinal cord injury; Acute or chronic cancer; Illness in eye; Virus infections; Cardiopathy; Tuberculosis; Or kidney or kidney trouble; And bronchitis.

Compound described herein is the inhibitor of kinase activity, and at the treatment obstacle disease relevant with unsuitable kinase activity, especially when treating and prevent by kinase mediated morbid state, have a treatment benefit.Therefore, the invention provides adjusting, especially suppress wherein that kinases has the method for the signal transduction pathway of important function.Said method generally includes to bestow the experimenter or make expresses the following material of said kinase whose cells contacting: the compound described herein of effective dose or its prodrug or its acceptable salt, hydrate, solvate, N-oxide and/or composition, thus regulate or the inhibition signal transduction pathway.Said method also is used to regulate, be particularly useful for suppressing the downstream process or the cellular response that are caused by specific signal transduction of kinases pathway activation.It is to characterize, cause or relevant with it disease that the signal transduction pathway that is relied on by said kinases to treatment or prevention activates, and said method is environment or in vivo implement as a kind of methods of treatment in the environment in vitro also.

2. pharmaceutical composition

For the therapeutical uses of the compound that this paper provides that comprises formula (I) compound or its pharmaceutically acceptable salt, solvate, N-oxide, prodrug and isomer, these compounds are individually dosed or as the part of pharmaceutical compositions administration with the treatment effective dose.Therefore, this paper provides the pharmaceutical composition of the compound that comprises that at least a this paper provides, and this pharmaceutical composition comprises: at least a in formula (I) compound, its pharmaceutically acceptable salt and/or the solvate; And, one or more pharmaceutically acceptable carriers, thinner, adjuvant or excipient.In addition, said compound and composition individually dosed or with one or more other healing potion combination medicine-feedings.The medication of said compound and composition includes, but is not limited to administration in administration in intravenous administration, suction, oral administration, rectally, parenterai administration, glass vivo medicine-feeding, subcutaneous administration, the muscle, intranasal administration, percutaneous dosing, topical, eye drops, the cheek, tracheae administration, bronchi administration, administration in sublingual administration or ear.The compound that this paper provided comprises with known pharmaceutical formulations form administration: peroral administration lozenge, capsule or elixir; The suppository of rectally; The sterile solution or the suspension of administration in parenterai administration or the muscle; The lotion of topical, gel, ointment or emulsifiable paste, or the like.

The treatment effective dose especially will be looked the order of severity, the experimenter's of disease, the disease of performance the tiring of age and relevant health status, the drug compound of giving, mode of administration and desired therapeutic effect and different.Required dosage also will be looked mode of administration, particular condition to be treated and desired effects and be different.

The pharmaceutically acceptable salt form comprises pharmaceutically acceptable acid/anion salt or alkali formula/cationic salts.Pharmaceutically acceptable acid/anion salt comprises acetate; Benzene sulfonate; Benzoate; Bicarbonate; Biatrate; Bromide; The edetic acid(EDTA) calcium salt; Camsilate; Carbonate; Chloride; Citrate; Dihydrochloride; Edetate; Ethanedisulphonate; Estolate; Esilate; Fumarate; Gluceptate; Gluconate; Glutamate; To hydroxyl acetylamino phenyl-arsonate (glycollylarsanilate); Hexyl resorcin salt (hexylresorcinate); Hydrobromate; Hydrochloride; Hydroxynaphthoate; Iodide; Isethionate; Lactate; Lactobionate; Malate; Maleate; Malonate; Mandelate; Mesylate; Methylsulfate; Mucate; Naphthalene sulfonate; Nitrate; Embonate; Pantothenate; Phosphate/phosphor acid hydrogen salt; Polygalacturonate; Salicylate; Stearate; Subacetate; Succinate; Sulphate; Disulfate; Tannate; Tartrate; Teoclate; Toluene fulfonate; With the triethyl group salt compounded of iodine.Pharmaceutically acceptable alkali formula/cationic salts comprises sodium salt, sylvite, calcium salt, magnesium salts, diethanolamine salt, N-methyl-D-glucamine salt, L-lysine salt, L-arginine salt, ammonium salt, ethanolamine salt, piperazine salt and triethanolamine salt.

Pharmaceutically-acceptable acid addition is to be formed by the free alkali form of formula (I) compound and suitable inorganic acid or organic acid reaction, and wherein inorganic acid or organic acid include, but is not limited to hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetate, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, naphthalene sulfonic acids (for example 2-naphthalene sulfonic acids) or caproic acid.The pharmaceutically-acceptable acid addition of formula (I) compound can comprise or for (for example) hydrobromate, hydrochloride, sulphate, nitrate, phosphate, succinate, maleate, formates, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, tosilate, benzene sulfonate, mesylate, esilate, naphthalene sulfonate (for example, 2-naphthalene sulfonate) or caproate.

Can be respectively by the free acid or the free alkali form of corresponding base addition salts or acid-addition salts prepare The compounds of this invention.For example, the The compounds of this invention that is the acid-addition salts form can be handled through suitable alkali (for example, Ammonia, sodium hydroxide etc.), is converted into corresponding free alkali.The The compounds of this invention that is the base addition salts form can be handled through suitable acid (for example hydrochloric acid etc.), is converted into corresponding free acid.

The prodrug of The compounds of this invention can be by being the known method preparations of those of ordinary skills; For example; Referring to people such as Saulnier, (1994), Bioorganic and Medicinal Chemistry Letters; Vol.4, p.1985 (its whole teaching content is incorporated herein with way of reference).

The protected derivative of The compounds of this invention can be by preparing for the known mode of those of ordinary skills; For example; Referring to T W.Greene, " blocking group in the organic chemistry (the 3rd edition) " (Protecting Groups in Organic Chemistry, 3 ^RdEdition), John's prestige found a state border publishing company (John Wiley and Sons, Inc.), 1999 (its whole teaching content is incorporated herein with way of reference).

Can be through racemic mixture and the reaction of optical activity resolving agent that makes The compounds of this invention; To form a pair of diastereo-isomerism compound; Further separate said diastereoisomer and reclaim the optical voidness enantiomter, thereby this compound is become its single stereoisomer.Referring to Jean Jacques, Andre Collet, Samuel H.Wilen; " enantiomter, racemic modification and fractionation " (Enantiomers; Racemates and Resolutions); John's prestige border publishing company that founds a state, 1981 (its whole teaching content is incorporated herein with way of reference).

Formula (I) compound can be used the step preparation described in this paper and the instance.In certain embodiments, formula (I) compound is prepared by the following step: (a) randomly The compounds of this invention is converted into pharmaceutically acceptable salt; (c) randomly the salt form of The compounds of this invention is converted into salt-independent shape; (d) randomly the not oxidised form of The compounds of this invention is converted into pharmaceutically acceptable N-oxide; (e) randomly split the single isomer of The compounds of this invention from the mixture of isomer; (f) randomly with the present invention not derived compounds be converted into pharmaceutically acceptable prodrug derivant; (g) randomly the prodrug derivant of The compounds of this invention is converted into its non-derivative form.

The teaching content of whole patents that this paper quoted, the application case of publication and list of references all is incorporated herein with way of reference.

Embodiment

Instance

By the further illustration the present invention of following instance, said instance has been explained the preparation of formula of the present invention (I) compound.These instances are only started from the purpose of explaination, and are not intended to be regarded as limit by any way the present invention.It will be understood by a person skilled in the art that, under the situation that does not change the scope of the invention, can make variation and modification.

General scheme 1 (method I)

General scheme 2 (method II)

General scheme 3 (acid amides is synthetic)

General scheme 4 (intermediate 5 and 9)

Should be understood that these instances only from the purpose of explaination, should not be regarded as limiting by any way the present invention.

Following instance is composed consistent with the compound with this paper chemical formula with the nuclear magnetic resonnance (NMR) that the compound that the instance in being set forth in this paper is set forth obtains with mass spectral analysis (MS).

Liquid chromatography-mass spectrography (LC-MS) method:

1, sample moves having in Agilent science and technology (Agilent Technologies) 6120MSD system of Zorbax Eclipse XDB-C18 (3.5 μ) reversed-phase column (4.6x50mm), and at room temperature with 1.5mL/ minute flow velocity operation.

2, flowing phase is used solvent orange 2 A (water/0.1% formic acid) and solvent B (acetonitrile/0.1% formic acid).

3, use electron spray ionisation method (ESI) record mass spectrum (m/z).

Proton N MR spectrum:

Except as otherwise noted, otherwise all ¹H NMR spectrum is all moved on Varian series Mercury 300MHz.All observed protons all are reported as the PPM (ppm) of low of tetramethylsilane, and the common abbreviation of using main peak to indicate: for example s (unimodal), d (bimodal), t (triplet), q (quartet), m (multiplet) and br (broad peak).

1-(2-chloro-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester: the preparation of intermediate 1

Under the room temperature, to 3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester 2 (3.15g, 20.5mmol) be stored in add in the solution of anhydrous acetonitrile potash (5.7g, 41mmol) with 2,4-two chloro-5-fluorine pyrimidines 1.Institute is produced suspension heated 3 hours down at 80 ℃, and with LC-MS or thin layer chromatography (TLC) monitoring reaction.Dilute with ethyl acetate then, and use brine wash.Collected organic layer is used anhydrous sodium sulfate drying, under vacuum (in vacou), carries out partial concentration subsequently.In enriched product, add n-hexane, to form light yellow precipitate.Collect the solid that is produced through filtering, and, carry out high vacuum dry subsequently, to obtain the target intermediate 1 of 4.9g (85%) with the n-hexane flushing; MS (ESI) m/z 285 [M+H] ⁺

The preparation of (1-(2-chloro-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol (intermediate numbering 2)

Under the ice bath cooling; (4.9g 17.2mmol) is stored in and slowly adds the 1M solution that 38mL (38mmol) Di-Isobutyl aluminum hydride (DIBAL) is dissolved in toluene in the solution of 60mL anhydrous tetrahydro furan (THF) to 1-(2-chloro-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester 1.After stirring 2 hours under the same temperature, should reaction through the cancellation of slow interpolation 1N-NaOH solution.Then, with the ethyl acetate dilution, and use brine wash.Collected organic layer is used anhydrous sodium sulfate drying, and concentrates in the vacuum lower part subsequently.To wherein adding n-hexane, to form light yellow precipitate.Collect the solid that is produced through filtering, and with the n-hexane flushing, and carry out high vacuum dry subsequently, to obtain 3.7g (90%) intermediate numbering 2; ¹H NMR (300MHz, CDCl ₃) δ 8.57 (1H, d, J=3.3Hz), 8.52 (1H, s), 7.94 (1H, s), 4.72 (2H, s); MS (ESI) m/z 243 [M+H] ⁺

The preparation of 1-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-carboxylate methyl ester (compound 1)

1-(2-chloro-5-methylpyrimidine-4-yl)-1H-pyrroles-3-carboxylate methyl ester (intermediate numbering 1) (300mg packs in 2 blind nut sample bottles (2dram vial); 1.20mmol), 3; 4, and the 5-trimethoxy-aniline (240mg, 1.32mmol), 540mg (3.9mmol) potash, Pd (dppf) Cl ₂(50mg), (±)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl (BYNAP) (70mg) with the no Shui diox of 4mL.After the degassing of nitrogen bubbling, reactant mixture was heated 4 hours down at 100 ℃.Remove the insoluble matter that is produced through filtering.Concentrated filtrate under vacuum is subsequently by the silica gel chromatograph purifying, with the compound number 1 (291mg, 61%) of the solid that obtains being white in color; MS (ESI) m/z 399 [M+H] ⁺

The preparation of 1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester (compound 2)

At room temperature (rt), to 3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester 2 (5.0g, 32.4mmol) be stored in add in the solution of anhydrous acetonitrile (60mL) potash (8.96g, 64.9mmol) with 4-chloro-2-(methyl mercapto) pyrimidine 11 (5.47g, 34.1mmol).The suspension that is produced was heated 8 hours down at 80 ℃, and with LC-MS or thin layer chromatography (TLC) monitoring reaction.Then, with the ethyl acetate dilution, and use brine wash.Collected organic layer is used anhydrous sodium sulfate drying, and under vacuum, concentrates subsequently.The residue that produces is used recrystallizing methanol, to obtain 7.88g (83%) 3-methyl isophthalic acid-(2-(methyl mercapto) pyrimidine-4-yl)-1H-pyrazoles-4-carboxylic acid, ethyl ester 12; MS (ESI) m/z 279 [M+H] ⁺(7.44g 26.7mmol) is dissolved in the 30mL carrene (DCM), and is cooled to 0 ℃ subsequently with the pyrazoles that is produced-4-carboxylate 12.Under same temperature, to said be cooled to add in 0 ℃ the solution 3-chloroperoxybenzoic acid (mCPBA, 13.2g, 58.8mmol).Reaction is warming up to room temperature, stirred 2 hours, subsequently through adding NaHCO ₃The saturated solution cancellation should reaction.Collected organic layer is used anhydrous sodium sulfate drying, and under vacuum, concentrates subsequently.The residue that is produced is recrystallized with isopropyl ether, to obtain 3-methyl isophthalic acid-(2-(methyl sulphonyl) pyrimidine-4-yl)-1H-pyrazoles-4-carboxylic acid, ethyl ester 13 (6.92g, 83%) that 7.88g (83%) is colorless solid; M/z 311 [M+H] ⁺(3.0g, 9.7mmol) (0.42mL, 9.7mmol) with 3, (1.4mL 9.7mmol) mixes in the 10mL n-butanol 5-dimethylaniline with acetate with gained sulfoxide 13.Heating concentrated mixture after 2 hours under vacuum under refluxing.Extract the residue that is produced with DCM, and use NaHCO ₃The saturated solution washing.Collected organic layer is used anhydrous sodium sulfate drying, and

Under vacuum, concentrate, use re-crystallizing in ethyl acetate subsequently, to obtain the compound number 2 that 0.86g (26%) is faint yellow solid; M/z 352 [M+H] ⁺

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid (compound 3)

At room temperature, (0.77g 2.2mmol) is stored in and adds 4mL 2N-NaOH solution in the solution of ethanol (10mL) to compound number 2.Reactant mixture was heated 2 hours under refluxing.When observing when not having starting material, under vacuum, remove ethanol.Use the DCM debris, use 1N-HC1 acidified aqueous solution water-bearing layer subsequently, to obtain faint yellow deposition.Collect the solid that is produced through filtering, carry out vacuum drying subsequently, with the compound number 3 (0.41g, 58%) that obtains being faint yellow solid; MS (ESI) m/z 324 [M+H] ⁺

The preparation of 1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-formaldehyde (intermediate numbering 3)

(0.56g 1.7mmol) is stored in the solution of 30mL dichloroethane (DCE) and adds MnO to compound number 4 ₂(1.5g, 10.2mmol).After stirring 4 hours under 60 ℃-70 ℃, make reactant mixture pass through diatomite (Celite) and fill up and use dichloromethane rinse.Under vacuum, concentrate said filtrating, with intermediate numbering 3 (0.44g, 80%) of the expectation that obtains being faint yellow solid; MS (ESI) m/z 326 [M+H] ⁺

The preparation of amine

The preparation of 2-(4-amino-2,6-dimethoxy phenoxy group) ethanol

To 2, the 6-syringol (1.54g, 10mmol) and bromoacetate (2.00g 12mmol) is stored in the solution of 15mL anhydrous dimethyl formamide (DMF) and adds 2.76g (20mmol) K ₂CO ₃This reactant mixture was stirred 20 hours down at 30 ℃.Under vacuum, concentrate said mixture, to remove volatile matter.Then, the residue that is produced with ethyl acetate (EtOAc) extraction, and use brine wash, with anhydrous sodium sulfate drying and, concentrated under vacuum subsequently, to obtain 2.2g (91.6%) 2-(2,6-dimethoxy phenoxy group) ethyl acetate.(1.2g 5mmol) is dissolved in silica gel (2.0g) and is stored in the suspension of 20mLDCM with the gained ester.At room temperature, in the solution that wherein obtains, dropwise add dense HNO ₃(20mL) be stored in the solution of 20mLDCM.After at room temperature stirring 1 hour, with its solution that obtains transfer in the separatory funnel and, subsequently the brown bottom is discarded in the 100g ice.Organic layer use brine wash above remaining, with anhydrous sodium sulfate drying and, concentrated under vacuum subsequently, to obtain 2-(2, the 6-dimethoxy-4 '-nitro-phenoxy) ethyl acetate that 1.4g (98%) is brown solid.(1.34g 4.7mmol) is dissolved among the anhydrous THF (20mL) with gained nitro-phenoxy ester.In ice bath cooling down, in resulting solution wherein slowly interpolation be stored in 1M DIBAL in the toluene be dissolved in solution (10.3mL, 10.3mmol).After at room temperature 1 hour, through add 1N-NaOH solution cancellation reaction and, extract with EtOAc subsequently.The gained organic layer is used anhydrous sodium sulfate drying, and passes through silicagel pad.Under vacuum, concentrate the filtrating that is produced, with 2-(2, the 6-dimethoxy-4 '-nitro-phenoxy) ethanol (1.01g, 88%) that obtain being faint yellow solid; MS (ESI) m/z 326 [M+H] ⁺

The preparation of (1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol (compound number 4)

In the 40mL bottle, pack into (1-(2-chloro-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol (intermediate numbering 2) (0.50g, 2.1mmol), 3, the 5-dimethylaniline (300mg, 2.4mmol), 850mg (6.2mmol) potash, Pd ₂(dba) ₃(86mg), (±)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl (BYNAP) (125mg) with the no Shui diox of 25mL.After the degassing of nitrogen bubbling, reactant mixture was heated 6 hours down at 100 ℃.Then, the insoluble matter that produces through removing by filter.Concentrated filtrate under vacuum is subsequently by the silica gel chromatograph purifying, with the compound number 4 (0.56g, 84%) of the solid that obtains being white in color; MS (ESI) m/z 328 [M+H] ⁺

The preparation of compound number 5-28

Following compound with general structure shown in the table 1 is by preparing to the said similar method of preparation compound number 4 preparations with said, and this method uses suitable 2-chlorine pyrimidine and suitable amine to prepare.The instance of spendable palladium catalyst comprises Pd (OAc) in this reaction ₂, Pd ₂(dba) ₃, Pd (dppf) Cl ₂, or Pd (PPh ₃) ₄And PdCl ₂(PPh ₃) ₂These catalyzer use with suitable part usually; This part is BINAP, 4 for example; The two diphenylphosphines-9 of 5-, 9-dimethyl oxa-anthracene (Xantphos), 2-dicyclohexyl phosphorus-2 ', 6 '-dimethoxy-biphenyl (S-Phos) or relevant mutually Pd part based on phosphine.Reaction is analyzed monitoring by TLC and LC-MS, and moves 3-16 hour down at 80 ℃ to 110 ℃.

Table 1

Formula I compound

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-N-(2-hydroxyethyl)-N, 3-dimethyl-1H-pyrazole-4-carboxamide: compound number 29

To acid compound numbering 3 (65mg, 0.2mmol) be stored in 2mL dry DMF and diisopropylethylamine (DIPEA) (100 microlitres, interpolation tetramethylurea hexafluorophosphoric acid ester (HBTU) in solution 0.6mmol) (83mg, 0.22mmol).This mixture was at room temperature stirred 15 minutes.At room temperature, to wherein add 2-(methylamino) ethanol (24mL, 0.3mmol).This reactant mixture is at room temperature stirred 3 hours, and use the TLC monitoring reaction.When observing when not having starting material, this reactant mixture dilutes with ethyl acetate, and with the 1N-NaOH washing, uses brine wash subsequently.Collected organic layer is used anhydrous sodium sulfate drying, and under vacuum, concentrate subsequently and, subsequently and by the silica gel chromatograph purifying, to obtain the be white in color target compound numbering 29 of solid of 53mg (70%); ¹H NMR (400MHz, DMSO-d ₆) δ 9.66 (s, 1H), 8.61 (s, 1H), 8.54 (d, J=5.2Hz, 1H), 7.19 (d, J=5.2Hz, 1H), 6.65 (s, 1H), 4.82 (br s, 1H), 3.56-3.48 (m, 2H), 3.14-2.95 (m, 2H), 2.31 (s, 3H), 2.26 (s, 6H); MS (ESI) m/z 381 [M+H] ⁺

The preparation of compound number 30-38

Following compound with general structure shown in the table 2 is by preparing with said preparation compound number 29 similar methods, use coupling agent; For example carbodiimide (EDCI), HBTU, HATU (2-(7-azo BTA)-N of coupling agent wherein; N; N ', N '-tetramethylurea hexafluorophosphoric acid ester), PyBop (hexafluorophosphoric acid BTA-1-base-oxygen base tripyrrole alkyl) or PyBrop (tripyrrole Wan base phosphonium bromide hexafluorophosphate)).Reaction is analyzed monitoring by TLC and LC-MS, and at room temperature moves 3-16 hour.

Table 2

Formula I compound

2-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methylamino) ethanol: compound number 39

Method I

At room temperature, with intermediate numbering 3 (65mg, 0.2mmol) and monoethanolamine (18 microlitres 0.3mmol) are stored in the solution stirring 20 minutes of 2mL carrene.At room temperature, in this solution, add NaBH (OAc) 3 (64mg, 0.3mmol).Should react and at room temperature stir 15 hours, use the 1N-NaOH cancellation subsequently.Use ethyl acetate extraction, and with twice of brine wash.Collected organic layer is used anhydrous sodium sulfate drying, concentrates in the vacuum lower part subsequently.The residue that is produced is by the silica gel chromatograph purifying, with the expectation compound number 39 (59mg, 74%) of the solid that obtains being white in color; ¹H NMR (300MHz, CDC1 ₃) δ, 8.38-8.40 (2H, m), 7.26 (1H, s), 6.67 (1H, s), 3.78 (2H, s), 3.70 (t, J=5.1Hz, 2H), 2.81 (t, J=5.1Hz, 2H), 2.36 (3H, s), 2.29 (6H, s); MS (ESI) m/z 371 [M+H] ⁺

Method II

2-(4-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) piperazine-1-yl) ethanol: compound 40

(0.70g 2.92mmol) is stored in the solution of 30mL dichloroethane (DCE) and adds MnO to intermediate numbering 2 ₂(2.67g, 17.5mmol).After stirring 4 hours under 70 ℃, make this reactant mixture through Celite pad, and use dichloromethane rinse.Concentrated filtrate under vacuum is to obtain being expectation intermediate numbering 4 (0.6g, 87%) of faint yellow solid.With intermediate numbering 4 (311mg, 1.32r) and 2-(piperazine-1-yl) ethanol (0.23g, the solution that 1.77mmol) is stored in 10mL carrene (DCM) at room temperature stirred 20 minutes.At room temperature, add NaBH (OAc) to this solution ₃(0.58g, 2.6mmol).This reaction solution was at room temperature stirred 3 hours, use the 1N-NaOH cancellation subsequently.Use ethyl acetate extraction, and with twice of brine wash.Collected organic layer is used anhydrous sodium sulfate drying, under vacuum, concentrates subsequently.The residue that produces by the silica gel chromatograph purifying, with expectation intermediate numbering 5 (0.42mg, 91%) of the solid that obtains being white in color.2-(4-((1-(2-chloro-5-methylpyrimidine-4-the yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperazine-1-yl) ethanol of in 2 blind nut sample bottles, packing into (intermediate numbering 5) (70mg; 0.2mmol), 3; 4.5-trimethoxy-aniline (48mg, 0.26mmol), 83mg (0.6mmol) potash, Pd (dppf) Cl ₂(8mg), the no Shui diox of BYNAP (12mg) and 3mL.After the degassing of nitrogen bubbling, this reactant mixture was heated 16 hours down at 100 ℃, and be cooled to room temperature.The insoluble matter that produces through removing by filter, concentrated filtrate under vacuum subsequently.The crineous residue that is produced is by silica gel chromatograph (5-15%MeOH/DCM) purifying, with the expectation compound 40 (74mg, 75%) that obtains being faint yellow solid; ¹H NMR (300MHz, CDC1 ₃) δ 9.43 (s, 1H), 8.34 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 7.18 (s, 2H), 3.77 (s, 9H), 3.61 (s, 2H), 3.45 (m, 2H), 3.21 (m, 2H), 2.38-2.32 (m, 8H), 2.19 (s, 3H), 2.03 (s, 3H); MS (ESI) m/z 497 [M+H] ⁺

The preparation of compound number 41-139

The following compound that has shown in the table 3 general structure be by with said preparation compound number 39 similar method I, use suitable aldehyde intermediate to number 3 and suitable amine HNR ⁵R ⁶Prepare, or by with said preparation compound number 40 similar method II, use suitable 2-chlorine pyrimidine intermediate numbering 5 and suitable amine H ₂NR ²Prepare.

Neopentanoic acid 1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) azetidine-3-base ester: compound number 93

At room temperature; To 1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol (compound number 91; 150mg; 0.34mmol) be stored in the solution of 2mL dry DMF and add 5mgN, N-dimethyl aminopyridine (DMAP) and trimethyl acetic anhydride (128mg, 0.68mmol).After at room temperature stirring 16 hours, under vacuum, concentrate this reactant mixture.The residue that is produced extracts with EtOAc, with the 2N-NaOH washing, uses anhydrous Na ₂SO ₄Drying concentrates under vacuum, and subsequently by chromatogram (5%-15%MeOH/DCM) purifying, with the expectation compound number 93 (98mg, 55%) that obtains being colorless solid; ¹H NMR (300MHz, CDC1 ₃) δ, 9.44 (s, 1H), 8.35 (2,1H), 7.37 (s, 1H), 7.30 (s, 1H), 7.19 (s; 2H), 4.88-4.94 (m, 1H), 3.78 (s, 6H), 3.76 (m, 1H), 3.61 (s, 3H), 3.57-.60 (m; 3H), 2.92 (m, 2H), 2.32 (s, 3H), 2.01 (s, 3H), 1.14 (s, 9H); MS (ESI) m/z 524 [M+H] ⁺

4-(3-((1,4-Diazesuberane-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methyl-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-2-amine: compound number 96

(200mg, 0.52mmol) with 1, (181 microlitres, the solution that 78mmol) is stored in the 4mL carrene at room temperature stirred 20 hours 4-Diazesuberane-1-carboxylic acid tertiary butyl ester with intermediate numbering 3.At room temperature, in this reactant, add NaBH (OAc) ₃(230mg, 1.0mmol).This reactant was at room temperature stirred 4 hours, use the 1N-NaOH cancellation subsequently.Use ethyl acetate extraction, and with twice of brine wash.Collected organic layer is used anhydrous sodium sulfate drying, under vacuum, concentrates subsequently.The residue that is produced is by the silica gel chromatograph purifying, to obtain being the compound number 96 (241mg, 82%) through tertbutyloxycarbonyl (Boc) protection of faint yellow solid.The gained compound is dissolved in the 3mL methyl alcohol.In the solution that this obtains, add 2.5mL4M-HC1.After at room temperature stirring 6 hours, the concentrated reaction mixture in the vacuum lower part adds EtOAc subsequently to form sediment.Collect the gained yellow solid through filtering, and with the EtOAC flushing, with the compound number 96 (230mg, 94%) that obtains being tri hydrochloride; ¹H NMR δ 11.13 (br s, 1H), 9.56 (s, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 7.44 (s, 1H), 7.19 (s, 2H), 4.20 (m, 2H), 3.78 (s, 6H), 3.61 (s, 3H), 3.40-3.52 (m, 10H), 2.36 (s, 3H), 2.13 (s, 3H); MS (ESI) m/z 467 [M+H] ⁺

4-(3-((1,4-Diazesuberane-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methyl-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-2-amine: compound number 97

At room temperature, to compound number 96 (42mg 0.07mmol) is stored in the N that adds catalytic amount in the solution of 1mL acetonitrile and diisopropylethylamine (83 microlitre), N-dimethyl aminopyridine and trimethyl acetic anhydride (28 microlitres, 0.14mmol).After at room temperature stirring 16 hours, under vacuum, concentrate this reactant mixture.The residue that is produced extracts with EtOAc, with the 2N-NaOH washing, uses anhydrous sodium sulfate drying, under vacuum, concentrates, subsequently by chromatogram (5%-15%MeOH/DCM) purifying, with the expectation compound number 97 (29mg, 72%) that obtains being colorless solid; ¹H NMR (300MHz, CDC1 ₃) δ, 9.44 (s, 1H), 8.35 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.19 (s, 2H), 3.77 (s, 6H), 3.61 (s, 3H), 3.49-3.52 (m, 6H), 2.73 (m, 2H), 2.33 (s, 3H), 2.04 (s, 3H), 1.76 (m, 2H), 1.18 (s, 9H); MS (ESI) m/z551 [M+H] ⁺

Table 3

Formula I compound

Biological analysis

1, kinase inhibition check

The test The compounds of this invention suppresses the ability of kinases panel, and said kinases panel includes, but is not limited to spleen tyrosine kinase (SYK), ζ chain related protein kinase 70 (ZAP70), PTK2B protein tyrosine kinase 2 (PYK2), focal adhesion kinase (FAK), Ma Luoni (maloney) provirus integration kinases 1 (PIM1), transfection rearrangement kinases (RET), Fms appearance EGFR-TK 3 (FLT3), Janus kinases 2 (JAK2) and rich leucine and repeats kinases 2 (LRRK2).

FLT3 is the member in III receptor EGFR-TK (RTK) family, and the part of FLT3 is by marrow stromal cell and other cellular expression.The part of FLT3 and other growth factor synergy are to stimulate the propagation of stem cell, CFU-GM, dendritic cells and natural killer cell.FLT3 relates to hematopoietic disorders property disease; Said hematopoietic disorders property disease is to comprise the preceding obstacle disease of cancerating of myeloproliferative disorder property disease, for example piastrenemia, primary thrombocytosis (ET), the life of angiogenesis medullization, myelofibrosis (MF), follow myelofibrosis (MMM), chronic idiopathic myelofibrosis (IMF) and polycythemia vera (PV), the cytopenia that medullization gives birth to and cancerate before myeloproliferative disorder syndrome.Hematologic malignancies comprises leukemia; Lymphoma (Fei Huoqijinshi (non-Hodgkin ' s) lymphoma); Hodgkin's disease (being also referred to as hodgkin's lymphomas); And myeloma (ALL (ALL) for example; Acute myelogenous leukemia (AML); Acute promyelocytic leukemia (APL); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); CNL (CNL); Acute undifferentiated cell leukemia (AUL); Anaplastic maxicell property lymphoma (ALCL); Prolymphocytic leukemia (PML); Teenager's grain-monocytic leukemia (JMML); Adult T cell ALL; First becoming impatient property myeloid leukemia (AML/TMDS) with the performance of three pastern bone marrow DHs; Mixed lineage leukemia (MLL); Myelodysplastic syndrome (MDS); Myeloproliferative disorder property disease (MPD); Huppert's disease (MM); And medullary sarcoma).

RET is the neurotrophic factor that is derived from glial cell-line (GDNF) family member's of extracellular signaling molecule (GFL ' s) a acceptor.The RET signal transduction is extremely important for the normal development of kidney and enteric nervous system.The generation of the sudden change of RET afunction property and congenital megacolon (Hirschsprung ' s disease) is relevant; And RET function gain mutation is relevant with various types of cancers generations, comprising medullary carcinoma of thyroid gland and II type and III type MEN,muitiple endocrine neoplasms.

Spleen tyrosine kinase (SYK) is the member of EGFR-TK SYK family, and said EGFR-TK is non-recipient cell kytoplasm EGFR-TK, has the peculiar pair of SH2 domain that is separated by link field.SYK has important function in transmitting from the signal that comprises various kinds of cell surface receptors such as CD74, Fc acceptor and integrin.The SYK dysfunction relates to the malignant tumor of hematopoiesis system incident.Know that in the industry several transforming virus for example are prone to Epstein-Ba Er (Epstein-Barr) virus, bovine leukemia virus and MMT virus and all contain " immunity receptor tyrosine activates motif (ITAM) " that causes SYK to activate.

ZAP70 is the enzyme that belongs to protein tyrosine kinase family, and has important function aspect thymic cell development, T-cell development and the lymphocyte activator.After T-cell antigen receptor (TCR) was upset, phosphorylation took place in ZAP70 on tyrosine residue, and in the initial step of TCR Mediated Signal Transduction, played a role with Src family kinase, Lck and Fyn combination.The ZAP70 gene mutation causes selectivity T-cell defect, and this is that a kind of the disappearance by the positive T-cell selective of CD8-is the serious combination immune deficiency disorder that characterizes.

PYK2 is the cytoplasm protein EGFR-TK, participates in the activation that calcium causes protein kinase (map kinase) signal transduction pathway of ion channel adjusting and the activation of people's mitogen.This encoded protein can be taken on important signal transduction intermediate between the downstream signal of the neuropeptide activated receptor that increases calcium current or neurotransmitter and adjusting neuronal activity.This encoded protein response intracellular calcium concentration increase, Nicotinic Acetylcholine Receptors activation, film depolarising or protein kinase C activation, and tyrosine phosphorylation fast takes place, thus be activated.The activation of PYK2 is related with the terminal kinase activity height of promotion c-Jun N-.PYK2 relates to such as following disease: osteoporosis, arthritis, myelomatosis, low osmotic pressure disease, sarcoma, BC, glioma, erythroleukemia and cancer.

FAK (by gene PTK2 coding) is a nonreceptor tyrosine kinase, integrates the signal from integrin and growth factor receptors.FAK has important function in regulating cell survival, growth, stretching, extension, migration and invasion and attack.By regulating and activate FAK in a plurality of tyrosine residue generation phosphorylations.The cancer that relates to mammary gland, colon, thyroid gland and prostate etc. is expressed in crossing of the mRNA of FAK and/or albumen.The phosphorylation of FAK increases in the malignant tissue.

JAK1 is the member of albumen-EGFR-TK (PTK) family, it is characterized in that immediately following second phosphotransferase dependency structure territory of the terminal existence of the N-of PTK domain.JAK1 participates in the signal transduction pathway of interferon-' alpha '/β and-γ.Complementary relation of interdependence in complementary relation of interdependence in the interferon-' alpha ' path between JAK1 and TYK2 activity, the interferon-path between JAK1 and JAK2 can reflect in the correct combination of interferon receptors complex these kinase whose demands.

JAK2 relates to the signal transduction that is undertaken by II cytokines receptor family (for example interferon receptors), macrophage colony stimulatory factor (GM-CSF) receptor family (IL-3R, IL-5R and GM-CSF-R), gp130 receptor family (for example IL-6R) and strand acceptor (for example Epo-R, Tpo-R, GH-R, PRL-R) member.JAK2 gene fusion TEL (ETV6) is (TEL-JAK2) relevant with leukemia with the PCM1 gene.In addition, the sudden change of JAK2 relates to polycythemia vera, primary thrombocytosis and other myeloproliferative disorder property disease.The sudden change of this JAK2 is to sport phenyl alanine at 617 valine, thereby makes hematopoietic cell to more responsive like growth factors such as erythropoietin(EPO) and TPOs.

JAK3 is the Janus Family Tyrosine Kinases, mainly in immunocyte, expresses.Tyrosine phosphorylation takes place via the interleukin-2-receptor mediation in JAK3, thereby is activated, and the signal conduction is carried out in this activation of JAK3 response.The sudden change of eliminating the JAK3 function causes autosome Reconstruction in Sever Combined Immunodeciency disease (SCID).The mouse of not expressing JAK3 has T-cell and the B-cell that various cell factors are not responded.Because JAK3 mainly expresses, therefore think that the effect of JAK3 in cytokine signaling has more restriction than other JAK in hematopoietic cell.JAK3 participates in signal transduction through acceptor, and this receptor has the common γ chain (γ C) of I cytokines receptor family (for example IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R).

Confirmed that it be a kind of of common proto-oncogene that the Ma Luoni provirus is integrated kinases (PIM-kinases), can be by the Ma Luoni retroviruse integration incident that takes place in the mouse by transcriptional activation, thus make infected mouse lymphoma occur.PIM1, PIM2 and PIM3 are serine/threonine kinases, usually in response to growth factor with cell factor and to the survival of hematopoietic cell with breed the generation effect.Crossing the incidence of disease that the transgenic mice of expressing PIM1 or PIM2 shows the T-cell lymphoma increases, and PIM1 or PIM2 made up expression with c-myc then the incidence of disease with the B-cell is relevant.Unusual PIM is expressed in the various human malignant tumour that comprises prostate cancer, hepatocellular carcinoma and cancer of pancreas and reports all to some extent.The PIM kinases is participated in the early stage atomization of complementary T-cell, and wherein complementary T-cell synergetic immunity in autoimmune disease, allergic reaction and tissue transplantation are repelled is replied.Except that in treatment of cancer and myeloproliferative disease, having the latent effect, the PIM inhibitor can be used to control immunocyte in other for example amplification under the pathological conditions such as autoimmune disease, allergic reaction and organ-graft refection's syndrome.

Method

The inhibition of SYK, ZAP70, PYK2, FAK, PIM1, RET, FLT3, JAK2 and LRRK2 kinase activity

With The compounds of this invention at 100% dimethyl sulfoxide (DMSO) (DMSO) (CALBIOCHEM ^TM) in initially be diluted to 10mM, be used for storing, and to prepare compound concentration be the kinase buffer solution in 1 μ M to the 10 μ M scope.The serial dilutions of The compounds of this invention is assigned to 96-orifice plate (GREINER BIOSCIENCES ^TM) in, each hole 6 μ L.Human FAK, RET, FLT3, JAK2 and LRRK2 (CARNA BIOSCIENCES with people's total length SYK, ZAP70, PIM1, PYK2 and the brachymemma of purifying ^TM) in kinase buffer liquid, dilute, and add in the compound solution, at room temperature preincubate 30 minutes (for PYK2 preincubate 1 hour).Then, with ATP (TEKNOVA ^TM) and substrate solution add (every hole 12 μ L) in the hole of containing compound solution and enzyme; Wherein substrate solution is PerkinElmer ^TMThe manufacturing substrate of suggestion, for example: for being used for the Ulight that SYK is ^TM-TK peptide, for being used for the Ulight that ZAP70, FAK and PYK2 are ^TM-PolyGT and for being used for the Ulight that PIM 1 is ^TM-CREBtide (PERKINELMER ^TM).Reactant mixture is hatched 1 hour (hatching 2 hours for PYK2).After hatching, add with ethylenediamine tetra-acetic acid (EDTA), water and Lance and detect buffer solution (PERKINELMER ^TM) stop bath (every hole 12 μ L) of preparation, to stop phosphorylation.Add stop bath, and after shaking 5 minutes, detection solution is added (every hole 12 μ L) in reactant mixture, hatched again 50 minutes; Wherein detect solution and contain antibody (PerkinElmer through the europium mark ^TMThe manufacturing substrate product of suggestion,, for example, be PT66, and be Anti-Creb for PIM1 for SYK, ZAP70, PYK2 and FAK), water and Lance detect buffer solution.After adding detection solution and hatching 50 minutes, through measuring, substrate phosphorylation is the function of the 665nm place emission wavelength of measurement.Except as otherwise noted, in Gradpad Prism 5, calculate the IC50 value of the IC50 value test compounds of test compounds and calculate, except as otherwise noted through Gradpad Prism 5.

The result

Formula (I) compound demonstrates useful pharmacological property.As used herein, 0% inhibition expression does not suppress (for example, finding in the control sample of handling without inhibitor) to kinase activity, and 100% inhibition expression suppresses kinase activity fully.

Protein kinase on formula (I) the compound counter plate demonstrates different inhibition degree.Some compound shows the inhibition percentage greater than 80% for one or more kinases under 1 μ M concentration, as shown in table 2.

For example, formula (I) compound 21 of 1 μ M concentration, i.e. (4-methyl isophthalic acid-(5-methyl-2-(3; 4; The 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol demonstrates the kinase activity of inhibition SYK (96.4%), Zap70 (54.6%), PYK2 (78.2%), FAK (70.7%) and PIM1 (71.2%), LRRK2 (93%), and inhibition FLT3 (IC50,1.9nM), RET (IC50; 50nM), KIT (137nM) and JAK2 (IC50, kinase activity 7.7nM) (referring to table 2).Table 2 shows percentage/mole inhibition that SYK, ZAP70, PYK2, FAK, PIM1, RET, FLT3, JAK2 and LRRK2 are suppressed by formula (I) representative compound.Use two kinds of known inhibitors of kinases R406 and staurosporin as positive control.

Table 2

Various kinase whose inhibition

* n.d. undetermined

2, TNF (TNF)-α discharges check

The influence that the test The compounds of this invention discharges the TNF-α in people's acute monocytic leukemia cell-line (THP-1) is with the latent effectiveness of explaination The compounds of this invention on cellular level.TNF-α is the cell factor of participating in systemic inflammatorome, and is the member who stimulates in one group of cell factor of acute phase response.The main effect of TNF-α is to regulate immunocyte.Apoptosis-induced cell death of known TNF-α and inflammation, and suppress infantile tumour generation and virus replication.The imbalance of TNF-α, especially excessive the generation relate to multiple human diseases, autoimmune disease, inflammation, arthritis and cancer.

Control generation or the release of TNF-α by the stimulus type of cellular response.And the active generation of participating in mediation TNF-α of SYK.When being stimulated by IgG, the mode that cell relies on SYK increases the generation (that is, SYK relies on path) of TNF-α.Yet when being stimulated by lipopolysaccharides (LPS), cell generates TNF-α with the mode of the non-dependence of SYK.

Method

The influence that the test The compounds of this invention discharges TNF-α in the THP-1 cell.The TNF-α that relies on for SYK discharges check (promptly; Stimulate via IgG), use the THP-1 cell that is derived from the person monocytic cell, this THP-1 cell derives from American Type Culture Collection (American Type Culture Collection) (ATCC; The Manassas, Virginia (VA)).This cell-line is with containing 10% hyclone (FBS; GIBCO ^TM) and the Loews of 0.05mM 2 mercapto ethanol dimension park memorial institute (RPMI) culture fluid (GIBCO ^TM) cultivate.With the THP-1 cell with 1x 10 ⁵Individual cell/100uL/ hole is seeded in human IgG (10 μ g/ holes, INVITROGEN ^TM) in 96 well culture plates of coating, and add the compound of serial dilution subsequently.Cultivation is after 18 hours down at 37 ℃, and the collection supernatant is measured the TNF-alpha levels by enzyme-linked immunosorbent assay (ELISA).Remaining cell carries out MTT (yellow tetrazolium salts) check, to measure the cytotoxic effect of compound.

Discharge check (promptly via lipopolysaccharides (LPS)-stimulations) for the TNF-α of the non-dependence of SYK, use is derived from person monocytic cell's THP-1 cell, this THP-1 cell derive from American Type Culture Collection (ATCC, the Manassas, VA).This cell-line is with containing 10% hyclone (FBS, GIBCO ^TM) and the RPMI culture fluid (GIBCOTM) of 0.05mM2-mercaptoethanol cultivate.With the THP-1 cell with 1x10 ⁵Individual cell/100uL/ hole is seeded in the 96-well culture plate, and handles with lipopolysaccharides (1 μ g/mL), and adds the compound of serial dilution subsequently.Cultivation is after 18 hours down at 37 ℃, and the collection supernatant is measured the TNF-alpha levels by ELISA.Remaining cell carries out the MTT check, to measure cytotoxic effect.

The result

Formula (I) compound demonstrates useful pharmacological property.As used herein, employed control sample demonstrates 0% inhibition that TNF-α discharges when not having inhibitor.

With the mode (for example, IgG stimulates) that SYK relies on, the inhibition percentage of some formula (I) compound of 0.3 μ M concentration is higher than 50%.Particularly; The TNF-α that relies at SYK discharges check (promptly; IgG stimulates release) in, the The compounds of this invention numbering 82,132 and 133 of 0.3 μ M concentration demonstrates percentage and suppresses to be higher than the percentage inhibition that R406 (being a kind of inhibitors of kinases that is widely known by the people) demonstrates.

For example; Formula (I) compound number 133 is that (((2-(3 for 1-for (R)-1-; The 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol, the TNF-α that under concentration 0.3 μ M, demonstrates discharges the percentage inhibition that percentage suppresses to be higher than R406.The percentage of representative formula (I) compound of the present invention suppresses data and is shown in Table 3.

Table 3

TNF-α discharges inhibition

3, cell survival rate check: RET suppresses

The test The compounds of this invention is to the influence of various human cancer cell-lines (for example MTC-TT) cell survival rate, to explain usefulness of the present invention.

RET proto-oncogene coding receptor tyrosine kinase is used to accept the neurotrophic factor family member that the extracellular signaling molecule is derived from glial cell-line.The sudden change of RET afunction property is relevant with Hirschsprung ' s disease; The function gain mutation then relates to the generation of people's polytype cancer, comprises that thyroid gland encephaloid, MEN,muitiple endocrine neoplasms form 2A (MEN2A) and 2B (MEN2B) type, pheochromocytoma and parathyroid hyperplasia.

Method

Discuss for the cell survival rate that RET is relied on, use medullary carcinoma of thyroid gland cell-line (representing the MTC-TT of MEN2A) to test The compounds of this invention.Containing 15% calf serum (Thermo ^TMHyclon ^TM) and be supplemented with and cultivate the MTC-TT cell in the RPMI culture fluid of 2mM L-glutaminate.Make cell with 5x 10 ⁴The density in individual cell/100uL/ hole was grown 1 day in the 96-orifice plate in duplicate, and handled with the test compounds of variable concentrations.After the drug treating 2 days, use single solution 96 porocytes propagation detection kit (Cell Titer 96Aqueous One Solution Reagent) (Promega according to manufacturer's specification ^TM) measure the cell survival rate of MTC-TT.

The result

As used herein, employed control sample representes that cell survival rate suppresses 50% o'clock concentration (IC50) when not having inhibitor.

The inhibition scope of the formula of IC50 concentration (I) compound is greater than 100nM.Particularly, in the cancer cell system that RET induces, the inhibition level that compound 40 and 121 appears is greater than the inhibition level that is appeared by known inhibitors of kinases ZD6474 (Vandetinib) and Sutent (Sunitinib).

For example; In IC50 measures; Formula (I) compound 121 is that the rejection ratio that appears of 2-(4-(4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base amino)-2,6-dimethyl phenoxy) ethanol is by ZD6474 (AstraZeneca ^TM) and Sutent (Pfizer ^TM) inhibition that appeared is high more than 2 times (referring to table 4), wherein ZD6474 and Sutent are the antagonists of vascular endothelial growth factor receptor (VEGFR) and crust growth factor receptors (EGFR).The IC50 of representative formula (I) compound of the present invention suppresses data and is shown in Table 4.

Table 4

Cell survival rate

4, cell survival rate check: the FLT3-internal series-connection repeats the inhibition of (ITD)-positive cell

In people's acute leukemia cells system (MV4-11), the influence that the test The compounds of this invention suppresses FLT3-ITD.FLT3 mainly expresses in prematurity HPC and ripe myeloid cell, belongs to III receptor EGFR-TK (RTK) family that comprises KIT, FMS and PDGFR etc.FLT3 causes kinase activity to increase through combining to activate with part (FL), thereby activates the downstream signal transduction path that comprises STAT5, Ras and PI3 kinases etc.

It is the most frequent observed molecular defect in acute myelogenous leukemia (AML) that FLT3-ITD (internal series-connection repetition) undergos mutation in nearly membrane structure territory.Dimerization, autophosphorylation and the constitutive activation of the non-dependence of FLT3-ITD inducing ligand, and can transform hematopoietic cell.Clinically, known FLT3-ITD strengthens leukocytosis, increases the initial cell counting, increases recurrence rate, reduces DFS and relatively poor total survival rate.Therefore, FLT3-ITD is the molecular target of very attractive in the AML treatment.

Method

The test The compounds of this invention is to the influence of the cell survival rate of MV4-11 cell.The MV4-11 cell that is used for the expressing human FLT3-ITD of cell survival rate check derive from American Type Culture Collection (ATCC, the Manassas, VA).This cell-line is with containing 10% calf serum (BCS; Hyclone ^TM) and be supplemented with the RPMI culture fluid (HyClone of iron ^TM) cultivate.With the MV4-11 cell with 2x10 ⁴Individual cell concentration is seeded in the 96-well culture plate, and adds the compound of serial dilution subsequently.Cultivation is after 72 hours down at 37 ℃, and use is simplified 1 step check (ATPLite lstep assay) (Perkin-Elmer based on the quantitative ATP of living cells ATP ^TM) measure the survival rate of cell.Simultaneously, parallel cell liquid check (CellTiter Aqueous assay) (Promega that tires that carries out ^TM) as orthogonal test.Use nonlinear regression to calculate IC ₅₀Value, and with IC ₅₀Value defined is: compare with undressed control cells, make treated cell reduce by 50% required concentration (Prism in fluorescence or absorptance ^TMSoftware).

The result

Formula (I) compound demonstrates the inhibition greater than 10nM under IC50 concentration.Particularly, in the cancer cell system that FLT3ITD induces, the inhibition level that compound 91 and 93 appears is higher than the inhibition level of ZD6474 and Sutent.

For example; Compound 93 is a neopentanoic acid 1-((4-methyl isophthalic acid-(5-methyl-2-(3; 4; The 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) the IC50 rejection ratio Sutent (Pfizer (Pfizer)) and the PKC-412 (Novartis Co.,Ltd (Novartis)) of the basic ester of azetidine-3-be high more than 6 times, and wherein Sutent (Pfizer) and PKC-412 (Novartis) they are known vascular endothelial growth factor receptor (VEGFR) and crust growth factor receptors (EGFR) antagonist.The IC50 of representative formula (I) compound (for example, compound 91,93,96 and 97) suppresses data and is shown in Table 5.

Table 5

The survival rate of FLT3-ITD carcinogenic cells system

5, cell survival rate check: JAK2 suppresses

The influence that the test The compounds of this invention suppresses JAK2 among the HEL (HEL) is with the latent effectiveness of explaination The compounds of this invention on cellular level.Janus associated kinase (JAK) family that is made up of four kinds of different protein tyrosine kinase JAK1, JAK2, JAK3 and TYK2 has important function in cell survival, propagation and differentiation.The single sudden change V617F of JAK2 gene (valine-to the replacement of-phenyl alanine) produce the composing type kinase activity, and facilitate the hematopoiesis imbalance.Usually in myeloproliferative disorder property disease (MPD), detect the V617F sudden change of JAK2; Said myeloproliferative disorder property disease is one group of candidate stem cell clone obstacle disease; Comprise polycythemia vera (PV), primary thrombocytosis (ET) and idiopathic myelofibrosis (IMF), these diseases might be converted into acute myelogenous leukemia all.JAK2V617F is by the composition phosphorylation, and can when not having cell factor to stimulate, activate the downstream signal transduction.

JAK2 still is the crucial transmitter of the various kinds of cell factor and the transduction of growth factor receptors downstream signal.Particularly, but the signal transduction of JAK2 phosphorylated protein and activating transcription factor (STAT) family.After the STAT phosphorylation, dimerization taking place, and transfer in the nuclear, and in nuclear, combines DNA and regulate target gene expression.Known JAK2/STAT signal transduction relates to driving Cycle Regulation and anti-apoptotic path.

Method

The test The compounds of this invention is to the influence of hel cell survival rate.The hel cell that is used for the expressing human JAK2V617F of cell survival rate check derive from American Type Culture Collection (ATCC, the Manassas, VA).This cell-line is with containing 10% calf serum (BCS; Hyclone ^TM) and be supplemented with the RPMI culture fluid (HyClone of iron ^TM) cultivate.With hel cell with 2x 10 ⁴The concentration of individual cell is seeded in 96 well culture plates, and adds the compound of serial dilution subsequently.Cultivation is after 72 hours down at 37 ℃, and use is simplified 1 step check (Perkin-Elmer based on the quantitative ATP of living cells ATP ^TM) measure the survival rate of cell.Simultaneously, the parallel cell liquid check (Promega that tires that carries out ^TM) as orthogonal test.Use nonlinear regression to calculate IC ₅₀Value, and with IC ₅₀Value defined is: compare with undressed control cells, make treated cell reduce by 50% required concentration (Prism in fluorescence or absorptance ^TMSoftware).

The result

Formula (I) compound demonstrates the inhibition greater than 10nM under IC50 concentration.Particularly, the inhibition level that compound 21 and 24 appears is higher than the inhibition level of Sorafenib (Sorafenib) (Beyer Co., Ltd (Bayer)), and said Sorafenib is the inhibitors of kinases of Raf during a kind of known cancer cell is, VEGFR and PDGFR.

For example, compound 21 promptly the IC50 inhibition measured value of (4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol (referring to table 6, compound 139) than high about 10 times of Sorafenib (Bayer).The IC50 of representative formula (I) compound suppresses data and is shown in Table 6.

Table 6

Cell survival rate: JAK2 kinase inhibition

6, kinase inhibition in vitro

Defined in the human body up to 518 kinds of different kinases.In order to measure representative formula (I) compound, to 104 kinds of commercially available kinases (Ambit Biosciences to known kinase whose depression effect scope ^TM) compound 82 is tested.These 104 kinds of kinases comprise ABL1 (E255K)-phosphorylation, ABL1 (T315I)-phosphorylation, ABL1-phosphorylation, ACVR1B, ADCK3, AKT1, AKT2, ALK, AURKA, AURKB, AXL, BMPR2, BRAF, BRAF (V600E), BTK, CDK11, CDK2, CDK3, CDK7, CDK9, CHEK1, CSF1R, CSNK1D, CSNK1G2, DCAMKL1, DYRK1B, EGFR, EGFR (L858R), EPHA2, ERBB2, ERBB4, ERK1, FAK, FGFR2, FGFR3, FLT1, FLT3, FLT4, GSK3B, IGF1R, IKK-α, IKK-β, INSR, JAK2 (JH1 domain-catalysis), JAK3 (JH1 domain-catalysis), JNK1, JNK2, JNK3, KIT, KIT (D816V), KIT (V559D, T670I), LKB1, LRRK2, LRRK2 (G2019S), MAP3K4, MAPKAPK2, MARK3, MEK1, MEK2, MET, MKNK1, MKNK2, MLK1, MTOR, p38-α, p38-β, PAK1, PAK2, PAK4, PCTK1, PDGFRA, PDGFRB, PDPK1, PIK3C2B, PIK3CA, PIK3CG, PFM1, PIM2, PIM3, PKAC-α, PLK1, PLK3, PLK4, PRKCE, PYK2, RAF1, RET, RIOK2, ROCK2, RSK2, SNARK, SRC, SRPK3, SYK, TAK1, TGFBR1, TIE2, TRKA, TSSK1B, TYK2 (JH1 domain-catalysis), ULK2, VEGFR2, YANK3 and ZAP70.

The result

The inhibition activity of compound 82 is reported as the percentage of control sample, the activity that wherein less numeric representation is stronger.Table 7 pair 20 kinds of different kinases gather; These kinase whose activity are that (((2-(3 for 1-for (R)-1-owing to there being compound 82; The 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol, suppress and receive significance.As usual, be lower than 35% of control sample and promptly be considered to kinase activity and receive significance and suppress, because often use numerical value 35% as threshold value.

Table 7

Be lower than the kinase inhibition analysis of control sample 35%

Kinases	% suppresses	Kinases	% suppresses
				ABL1(T315I)	35	MLK1	22
AURKB	31	PDGFRB	1.8
				AXL	31	PLK3	11
FLT3	1.1	RET	32
				JAK2	3	SNARK	4.2
JAK3	5.4	SRPK3	25
				KIT	26	SYK	1
KIT(D816V)	0.45	TAK1	22
				KIT(V559D，T670I)	28	TYK2	21
MKNK2	34	ZAP70	34

Although the present invention has been carried out concrete displaying and has set forth with the illustration embodiment, it will be understood by a person skilled in the art that, can be under the situation that does not deviate from the protection domain of containing by the claims of enclosing of the present invention in the variation of wherein making various forms and details.

Claims

1. formula (I) compound or its pharmaceutically acceptable salt:

Formula (I)

Wherein:

X is CH or N;

R ¹Be selected from H, halogen, CN, C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) alkyl, wherein C ₁-C ₁₀Alkyl or halo (C ₁-C ₄) randomly warp replacement of alkyl;

R ³Be halogen, CN or R independently ⁷And

R ⁴Be selected from (CH ₂) _nOH, (CH ₂) _nNR ¹¹R ¹², C (O) NHR ⁷, C (O) NR ¹¹R ¹², C (O) OR ⁷, C (O) R ⁷, C (O) NR ⁷R ⁷, C (O) NR ⁷R ⁸, (CH ₂) _nNR ⁷R ⁷, WCH ₂) _nNR ⁷R ⁸, (CH ₂) _nCN, (CH ₂) _nSR ⁷, (CH ₂) _nS (O) _nR ⁷, or (CH ₂) _nS (O) _nNR ⁷R ⁷, wherein each n is 1 or 2 all independently;

Wherein:

Each R ¹⁰Be C (O) O (C ₁-C ₆) alkyl or halo (C ₁-C ₄) alkyl; And

R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms:

Iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly independently are selected from R through 1-4 at one or more substitutable carbon atoms place ⁵Or R ^5aGroup replace;

V) remove R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; A wherein said 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

2. compound according to claim 1, wherein R ²Be to be selected from following aryl: contain 0-3 the first monocyclic aryl of heteroatomic 5-6, wherein hetero atom is independently selected from nitrogen, oxygen or sulphur; Contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Contain the aryl bicyclic of 0-5 the first fractional saturation of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Or, contain the aryl bicyclic of the 8-10 unit fractional saturation of formamide or sulfonamide.

3. compound according to claim 2, wherein R ²Be to contain the heteroatomic 5-6 of 0-3 unit monocyclic aryl, wherein hetero atom is independently selected from nitrogen, oxygen or sulphur, and optional and independently through 1-4 R ⁵Or R ^5aGroup replaces.

4. compound according to claim 3, the first monocyclic aryl of wherein said 5-6 is phenyl or pyrimidine radicals, wherein phenyl or pyrimidine radicals are chosen wantonly and are selected from methyl, ethyl, phenyl, isopropyl, methoxyl group, hydroxyl-oxethyl, CF through 1,2 or 3 independently ₃, OC ₆H ₅, OCH ₂CH ₂NR ¹¹R ¹², OCH ₂CH ₂NR ⁷R ⁷, OCH ₂C ₆H ₅, OCH ₂C (O) NR ¹¹R ¹², OCH ₂C (O) NR ⁷R ⁷, OSO ₂CH ₃, SO ₂CH ₃, SO ₂NHCH ₃, or NR ¹¹R ¹²Group replace.

5. compound according to claim 2, wherein R ²Be to contain 0-5 the first aryl bicyclic of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; Wherein said 8-10 unit aryl bicyclic is selected from indyl, indazolyl, benzothienyl, benzothiazolyl, benzofuranyl, naphthyl or quinolyl, and optional and be selected from alkyl, aryl, heteroaryl, alkoxyl, halogen, CF at commutable carbon atom or 1,2 or 3 at nitrogen-atoms place independently ₃, OCF ₃, or SO ₂CH ₃Group replace, wherein alkyl, aryl or heteroaryl randomly replace through hydroxyl, amino or sulfone.

6. compound according to claim 2, wherein R ²Be the aryl bicyclic that contains 0-5 the first fractional saturation of heteroatomic 8-10, wherein hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide or sulfone; The aryl bicyclic of wherein said 8-10 unit fractional saturation has and non-aromatic carbocyclic ring or heterocyclic fused phenyl ring, and optional and independently at commutable carbon atom place 1,2 or 3 be selected from alkyl, aryl, heteroaryl, alkoxyl, halogen, CF ₃, OCF ₃, or SO ₂CH ₃Group replace, the wherein said aryl bicyclic that has with the 8-10 unit fractional saturation of non-aromatic carbocyclic ring or heterocyclic fused phenyl ring is selected from dihydro indenyl, tetralyl or dihydrobenzo bioxin base.

7. compound according to claim 1, wherein R ⁴Be C (O) OR ⁷, and R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl or C ₃-C ₁₀Alkynyl is wherein by R ⁷Represented group is optional and be selected from hydroxyl, halogen, amino, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.

8. compound according to claim 7, wherein R ⁷Be C ₁-C ₁₀Alkyl, this C ₁-C ₁₀Alkyl is randomly through halogen, hydroxyl, amino, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆Alkyl amino replaces.

9. compound according to claim 8, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

10. compound according to claim 8, wherein R ³Be selected from H, cyclopropyl, isopropyl, furyl, methyl, CF ₃, or phenyl.

11. compound according to claim 1, wherein R ⁴Be C (O) NHR ⁷, and R ⁷Be H, C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical; Wherein said C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical are optional and be selected from halogen, amino, aryl, cycloalkyl, heterocyclic radical, alkyl, R through 1-4 independently ⁹, or R ¹⁰Group replace.

12. compound according to claim 11, wherein R ⁷It is aryl; Wherein said aryl is a phenyl, and this phenyl is optional and be selected from methyl, methoxyl group, CF through 1,2 or 3 independently ₃, or SO ₂CH ₃Group replace.

13. compound according to claim 11, wherein R ⁷Be C ₁-C ₁₀Alkyl, wherein said C ₁-C ₁₀Alkyl randomly is selected from amino, halogen, hydroxyl, phenyl, C through 1-3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl amino or two C ₁-C ₆The group of alkyl amino replaces.

14. compound according to claim 11, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

15. compound according to claim 11, wherein R ³Be selected from H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

16. compound according to claim 1, wherein R ⁴Be C (O) NR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms:

Iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein saidly do not contain heteroatomic 9-10 unit's ring filling or fractional saturation two rings randomly independently are selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace; Or

Iv) remove R ¹¹And R ¹²Also contain 1-5 saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute's key knot, wherein said hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfoxide, sulfone, formamide or sulfonamide.

17. compound according to claim 16, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute's key knot, the first ring of wherein said 3-8 is optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.

18. compound according to claim 17, the wherein said R that removes ¹¹And R ¹²Not containing the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of institute key knot is 4-6 unit ring; The first ring of wherein said 4-6 is azelidinyl, pyrrolidinyl or piperidyl, and this azelidinyl, pyrrolidinyl or piperidyl are optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.

19. compound according to claim 18, wherein said R ⁵Or R ^5aBe hydroxyl, CH ₂OH, CH ₂CH ₂OH, NH ₂, NHR ⁷, NHCOR ⁷, NHC (O) NHR ⁷, or NR ⁷R ⁷

20. compound according to claim 19, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

21. compound according to claim 19, wherein R ³Be selected from H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

22. compound according to claim 1, wherein R ⁴Be (CH ₂) _nNR ⁷R ⁷, and R ⁷Be H, C independently ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical; Wherein said C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₃-C ₁₀Alkynyl, C ₃-C ₁₂Cycloalkyl, C ₅-C ₁₂Cycloalkenyl group, aryl, haloalkyl, heteroaryl or heterocyclic radical are chosen wantonly and are replaced through 1-4 group that is selected from hydroxyl, halogen, amino, aryl, cycloalkyl, heterocyclic radical or alkyl independently.

23. compound according to claim 22, wherein R ⁷Be H or C independently ₁-C ₁₀Alkyl.

24. compound according to claim 23, wherein R ⁷Be C ₁-C ₁₀Alkyl, this C ₁-C ₁₀Alkyl randomly replaces through phenyl.

25. compound according to claim 24, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

26. compound according to claim 25, wherein R ³Be selected from H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

27. compound according to claim 1, wherein R ⁴Be (CH ₂) _nNR ¹¹R ¹², and R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms:

Iii) remove R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, wherein said saturated or fractional saturation two rings of heteroatomic 9-10 unit that do not contain randomly independently are selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace;

28. compound according to claim 27, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ^{12 institutes}Do not contain the saturated or fractional saturation ring of heteroatomic 3-8 unit beyond the nitrogen-atoms of key knot, the first ring of wherein said 3-8 is optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.

29. compound according to claim 28; Saturated or the fractional saturation ring of wherein said 3-8 unit is the 4-6 unit ring that is selected from azelidinyl, pyrrolidinyl or piperidyl, and this azelidinyl, pyrrolidinyl or piperidyl are optional and be selected from hydroxyl, halogen, OC (O) R at one or more substitutable carbon atoms place through 1-2 independently ⁷, CH ₂OH, CH ₂CH ₂OH, NH ₂, NR ⁷R ⁷, NHC (O) NHR ⁷, NHSO ₂R ⁷, C (O) OR ⁷, or C (O) NHR ⁷Group replace.

30. compound according to claim 27, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation ring of heteroatomic 5-8 unit beyond the nitrogen-atoms of institute's key knot; A wherein said 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 5-8 of the wherein said 1-3 of containing unit is saturated or the fractional saturation ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

31. compound according to claim 30, wherein said 5-8 unit ring is morpholinyl, thiomorpholine base, piperazinyl or high piperazinyl, wherein piperazinyl or high piperazinyl optional and independently at the nitrogen-atoms place through hydroxyl, C ₁-C ₁₀Alkyl, CH ₂CH ₂OH, C (O) R ⁷, C (O) NHR ⁷, WO ₂R ⁷, SO ₂NHR ⁷, or C (O) OR ⁷Replace.

32. compound according to claim 27, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Do not contain saturated or fractional saturation two rings of heteroatomic 9-10 unit beyond the nitrogen-atoms of institute key knot, saturated or fractional saturation two rings of wherein said 9-10 unit randomly are independently selected from R at one or more substitutable carbon atoms place through 1-4 ⁵Or R ^5aGroup replace.

33. compound according to claim 32, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms tetrahydroisoquinoline.

34. compound according to claim 33, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

35. compound according to claim 33, wherein R ³Be selected from H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

36. compound according to claim 27, wherein R ¹¹And R ¹²Nitrogen-atoms with their institute's key knots forms except that R ¹¹And R ¹²Also contain 1-3 the saturated or fractional saturation bridged ring of heteroatomic 6-14 unit beyond the nitrogen-atoms of institute's key knot; A wherein said 1-3 hetero atom is independently selected from nitrogen, oxygen, sulphur, sulfone or sulfoxide, and the heteroatomic 6-14 of the wherein said 1-3 of containing unit is saturated or the fractional saturation bridged ring optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace and at one or more instead nitrogen-atoms place through R ⁶Or R ^6aReplace.

37. compound according to claim 36, the wherein said R that removes ¹¹And R ¹²Also containing the saturated or fractional saturation bridged ring of 1-3 heteroatomic 6-14 unit beyond the nitrogen-atoms of institute key knot is 2; 5-diazabicylo [2.2.1] heptane base; This 2,5-diazabicylo [2.2.1] heptane base is optional and be selected from R at one or more substitutable carbon atoms place through 1-4 independently ⁵Or R ^5aGroup replace.

38. compound according to claim 36, wherein R ¹Be H, F, Cl, Br, CF ₃, or CH ₃

39. according to the described compound of claim 37, wherein R ³Be selected from H, methyl, cyclopropyl, isopropyl, furyl, CF ₃, or phenyl.

40. a compound, said compound is selected from:

1-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-carboxylate methyl ester;

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid, ethyl ester;

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-carboxylic acid;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrazoles-4-yl) methyl alcohol;

(1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrazoles-4-yl) methyl alcohol;

(1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol;

(1-(2-(2,3-dihydro-1H-indenes-5-base is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3,5-dimethyl-4-(2-(pyrrolidines-1-yl) ethyoxyl) phenyl amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3,5-dimethyl-4-Phenoxyphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

2-(4-(5-fluoro-4-(3-(hydroxymethyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-2,6-dimethyl phenoxy) ethanol;

(1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3, two (trifluoromethyl) phenyl aminos of 5-)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(5-fluoro-2-(naphthalene-2-base is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(5-chloro-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(4-cyclopropyl-1-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol;

(4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl alcohol;

2-(4-(4-(3-(hydroxymethyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base is amino)-2,6-dimethoxy phenoxy group) ethanol;

2-(4-(4-(4-(3-(hydroxymethyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base is amino)-2-aminomethyl phenyl) piperazine-1-yl) ethanol;

(S)-1-(4-(4-(3-(hydroxymethyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base is amino)-2-aminomethyl phenyl) pyrrolidines-3-alcohol;

(1-(5-fluoro-2-(4-(methyl sulphonyl) phenyl amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-(trifluoromethyl) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl alcohol;

(1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-phenyl-1H-pyrroles-3-yl) methyl alcohol;

(1-(5-fluoro-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-4-(furans-3-yl)-1H-pyrroles-3-yl) methyl alcohol;

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-N-(2-hydroxyethyl)-N, 3-dimethyl-1H-pyrazole-4-carboxamide;

1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-N, two (2-the hydroxyethyl)-3-methyl isophthalic acid H-pyrazole-4-carboxamides of N-;

(S)-(1-(2-(3,5-3,5-dimethylphenyl amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) (3-hydroxyl pyrrolidine-1-yl) ketone;

(R)-(1-(2-(3,5-3,5-dimethylphenyl amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) (3-hydroxyl pyrrolidine-1-yl) ketone;

N-(2-amino-ethyl)-1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-N-(3, the 5-3,5-dimethylphenyl)-1H-pyrazole-4-carboxamide;

(1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrazoles-4-yl) (piperidines-1-yl) ketone;

(S)-1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-N-(1-hydroxy propane-2-yl)-3-methyl isophthalic acid H-pyrazole-4-carboxamide;

N-benzyl-1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrazole-4-carboxamide;

(R)-(1-(2-(3,5-3,5-dimethylphenyl amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) (3-hydroxyl pyrrolidine-1-yl) ketone;

2-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methylamino) ethanol;

2-(4-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) piperazine-1-yl) ethanol;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((4-cyclopropyl-1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

4-(4-((benzylamino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl) pyrimidine-2-amine;

4-(4-(3-((3-hydroxy azetidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-2,6-3,5-dimethylphenyl mesylate;

(R)-and 4-(4-(3-((3-hydroxyl pyrrolidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-N, the 2-dimethyl benzene sulfonamide;

(R)-1-((1-(2-(3,5-dimethyl-4-(2-(pyrrolidines-1-yl) ethyoxyl) phenyl amino) pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl) pyrrolidines-3-alcohol;

(S)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-carboxylic acid;

(R)-1-((1-(2-(3,5-dimethyl-4-Phenoxyphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

(R)-1-(1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-yl) urea;

1-((4-methyl isophthalic acid-(2-(2-methyldiphenyl base-4-base is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

1-((1-(2-(2,3-dihydro-1H-indenes-5-base is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

1-((4-methyl isophthalic acid-(2-(1-Methyl-1H-indole-5-base is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

(R)-1-((4-methyl isophthalic acid-(2-(1-Methyl-1H-indole-5-base is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

4-(3-((4,4-difluoro piperidines-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl) pyrimidine-2-amine;

(R)-2-(4-(4-(4-((3-hydroxyl pyrrolidine-1-yl) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl) pyrimidine-2--amino)-2,6-dimethyl phenoxy)-1-morpholine ethyl ketone;

2-(4-(4-(4-((3-hydroxy azetidine-1-yl) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl) pyrimidine-2--amino)-2,6-dimethyl phenoxy)-1-morpholine ethyl ketone;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-(pyrrolidines-1-ylmethyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

(S)-2-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methylamino) propane-1-alcohol;

4-(4-((cyclopropyl is amino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

4-(4-((cyclohexyl is amino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-(piperidines-1-ylmethyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-(morpholinyl methyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-((phenyl amino) methyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

4-(4-((3,4-dihydro-isoquinoline-2 (1H)-yl) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

4-(4-((benzyl (methyl) amino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

N ¹-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl) ethane-1, the 2-diamines;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(4-((4-fluorobenzene ethylamino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl) pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-((pyridin-4-yl methylamino) methyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

(S)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl) pyrrolidines-3-alcohol;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl) pyrrolidines-3-alcohol;

1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl) piperidines-4-alcohol;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-(piperidines-1-ylmethyl)-1H-pyrroles-1-yl) pyrimidine-2-amine;

1-((3-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrazoles-4-yl) methyl) aza-cyclobutane-3-alcohol;

4-(4-((benzylamino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-((4-methyl piperazine-1-yl) methyl)-1H-pyrazol-1-yl) pyrimidine-2-amine;

4-(4-((dimethylamino) methyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-((piperidin-4-yl is amino) methyl)-1H-pyrazol-1-yl) pyrimidine-2-amine tri hydrochloride;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-(3-sulfonyl-pyrrolidine-1-ylmethyl)-1H-pyrroles-1-yl) pyrimidine-2-amine;

4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

N-(3, the 5-3,5-dimethylphenyl)-5-fluoro-4-(3-methyl-4-(morpholinyl methyl)-1H-pyrroles-1-yl) pyrimidine-2-amine;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((1-(2-(3, the 4-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

(R)-2-(4-(5-fluoro-4-(3-((3-hydroxyl pyrrolidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-2,6-dimethyl phenoxy)-1-morpholine ethyl ketone;

3-(4-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) piperazine-1-yl)-3-OPN;

(R)-4-(3-((3-amino-pyrrolidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

1-((1-(5-fluoro-2-(naphthalene-2-base is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

1-((1-(2-(4-(benzyl oxygen base)-3, the 5-Dimethoxyphenyl is amino)-5-methylpyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

(R)-and 4-(5-fluoro-4-(3-((3-hydroxyl pyrrolidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-2,6-3,5-dimethylphenyl mesylate;

(R)-1-((1-(5-fluoro-2-(4-(2-hydroxyl-oxethyl)-3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

Acetate 1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3 base) methyl) azetidine-3-base ester;

Neopentanoic acid 1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) azetidine-3-base ester;

1-((4-cyclopropyl-1-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) urea;

4-(3-((1,4-Diazesuberane-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methyl-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-2-amine tri hydrochloride;

(S)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

2,2-dimethyl-1-(4-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl)-1,4-Diazesuberane-1-yl) propane-1-ketone;

1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

(S)-2-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methylamino) propane-1-alcohol;

4-(3-((benzylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-N-(3, the 5-Dimethoxyphenyl)-5-fluorine pyrimidine-2-amine;

(R)-1-((1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

4-(3-((dimethylamino) methyl)-4-(furans-3-yl)-1H-pyrroles-1-yl)-5-fluoro-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-2-amine;

1-((1-(2-(3, the 5-Dimethoxyphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

N-(3, the 5-Dimethoxyphenyl)-4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-fluorine pyrimidine-2-amine;

(R)-1-((1-(5-fluoro-2-(3-(trifluoromethyl) phenyl amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((1-(5-fluoro-2-(3-(trifluoromethyl) phenyl amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

2-(4-((1-(5-chloro-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperazine-1-yl) ethanol;

1-((1-(5-chloro-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

1-((1-(5-chloro-2-(4-(2-hydroxyl-oxethyl)-3, the 5-3,5-dimethylphenyl is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-methylpyrimidine-2-amine;

1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-methylpyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

2-(4-((1-(2-(4-(4-(2-hydroxyethyl) piperazine-1-yl)-3-aminomethyl phenyl is amino)-5-methylpyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperazine-1-yl) ethanol;

4-((1-(2-(4-(2-hydroxyl-oxethyl)-3, the 5-3,5-dimethylphenyl is amino)-5-methylpyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl)-N-methyl isophthalic acid, 4-Diazesuberane-1-formamide;

4-((1-(2-(4-(2-hydroxyl-oxethyl)-3, the 5-3,5-dimethylphenyl is amino)-5-methylpyrimidine-4-yl)-4-methyl-lH-pyrroles-3-yl) methyl)-1,4-Diazesuberane-1-formamide;

1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

(1-((4-methyl isophthalic acid-(5-methyl-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) piperidin-4-yl) methyl alcohol;

1-((1-(2-(3,5-dimethyl-4-(2 (pyrrolidines-1-yl) ethyoxyl) phenyl amino)-5-methylpyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

2-(4-(4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base is amino)-2,6-dimethyl phenoxy) ethanol;

4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-fluoro-N-(3-(trifluoromethyl) phenyl) pyrimidine-2-amine;

2-(4-(5-fluoro-4-(3-((3-hydroxy azetidine-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl) pyrimidine-2--amino)-2,6-dimethyl phenoxy)-1-(pyrrolidines-1-yl) ethyl ketone;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-(trifluoromethyl) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((1-(5-fluoro-2-(3,4, the 5-trimethoxyphenyl is amino) pyrimidine-4-yl)-4-(furans-3-yl)-1H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol;

4-(3-((dimethylamino) methyl)-4-phenyl-1H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-4-phenyl-1H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

N-(3, two (trifluoromethyl) phenyl of 5-)-4-(3-((dimethylamino) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-fluorine pyrimidine-2-amine;

(R)-1-((1-(2-(3, two (trifluoromethyl) phenyl aminos of 5-)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

1-((1-(2-(3, two (trifluoromethyl) phenyl aminos of 5-)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) piperidines-4-alcohol;

4-(3-((dimethylamino) methyl)-1H-pyrroles-1-yl)-N-(3, the 5-3,5-dimethylphenyl)-5-fluorine pyrimidine-2-amine;

(R)-1-((1-(2-(3, the 5-3,5-dimethylphenyl is amino)-5-fluorine pyrimidine-4-yl)-1H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol;

4-(3-(2,5-diazabicylo [2.2.1] heptan-2-ylmethyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-bromo-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-2-amine tri hydrochloride;

2-(4-((3-(2,5-diazabicylo [2.2.1] heptan-2-ylmethyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-methylpyrimidine-2-base is amino for 4-)-2,6-dimethyl phenoxy) ethanol tri hydrochloride;

4-(3-((1,4--Diazesuberane-1-yl) methyl)-4-methyl isophthalic acid H-pyrroles-1-yl)-5-chloro-N-(2, and 3-dihydrobenzo [b] [1,4] bioxin-6-yl) pyrimidine-2-amine;

1-((1-(5-chloro-2-(2,3-dihydrobenzo [b] [1,4] bioxin-6-base is amino) pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) aza-cyclobutane-3-alcohol; Or

(R)-1-((1-(2-(4,6-dimethyl pyrimidine-2-base is amino)-5-fluorine pyrimidine-4-yl)-4-methyl isophthalic acid H-pyrroles-3-yl) methyl) pyrrolidines-3-alcohol.

41. isomerism compound according to the said compound of claim 1.

42. a pharmaceutical formulations, said pharmaceutical formulations comprises the combination of compound according to claim 1 and pharmaceutically acceptable carrier, thinner or excipient.

43. one kind is to have the experimenter who needs to treat the method for protein kinase mediated disease, said method comprises to the compound according to claim 1 of said experimenter's administering therapeutic effective dose or its pharmaceutically acceptable salt; Wherein said protein kinase mediated disease is selected from by asthma; COPD; Adult respiratory distress syndrome (ARDS); Ulcerative colitis; Crohn's disease; Bronchitis; Dermatitis; Allergic rhinitis; Psoriasis; Chorionitis; Nettle rash; The epidermolysis obstacle disease; Collagenosis; Contact dermatitis; Eczema; Kawasaki disease; Brandy nose; Xue's lattice connect Cotard; Rheumatoid arthritis; Multiple sclerosis; Inflammatory bowel is prone to swash sick; The disease that AIDS virus is relevant; Lupus; Lymphoma; Osteosarcoma; Melanoma; Breast cancer; Kidney; Prostate cancer; Colorectal cancer; Thyroid cancer; Oophoroma; Cancer of pancreas; Neural cancer; Lung cancer; The cancer of the uterus; Human primary gastrointestinal cancers; Alzheimer disease; Parkinson's; Osteoporosis; Osteopenia disease; Malacosteon; Osteofibrosis; Paget disease; Diabetes; The blood vessel hyperplasia obstacle disease; Illness in eye; Cardiovascular disease; Restenosis; Fibrosis; Atherosclerotic; Arrhythmia; Pharyngalgia; Myocardial ischemia; Miocardial infarction; Heart or vascular knurl; Vasculitis; Apoplexy; Obstructive arteriopathy on every side; Reperfusion injury behind organ or tissue's ischemic; Endotoxin induction or operation property or traumatic shock; Hypertension; Valvular heart disease; In heart failure; Abnormal blood pressure; Vessel retraction; Aberrant angiogenesis; Graft rejection; With the sick group of being formed of the infection that comprises virus and fungal infection.

44. according to the described method of claim 43, the individually dosed or said compound according to claim 1 of wherein said compound according to claim 1 and one or more other treatment agent combination administration.

45. according to the described method of claim 43, wherein said compound according to claim 1 is via the following manner administration: administration in intravenous administration, subcutaneous administration, suction, oral administration, rectally, non-administration in enteral administration, glass vivo medicine-feeding, intramuscular administration, intranasal administration, percutaneous dosing, topical, ear, eye drops, the cheek, tracheae administration, bronchi administration or through sublingual administration.

46. an inhibition has the method for SYK, PYK2, FAK, ZAP70, PIM1, FLT3, RET, JAK2, JAK3, LRRK2, LRRK2 (G2019S), ABL1 (T315I), AURKB, AXL, FLT3, KIT, KIT (D816V), KIT (V559D, T670I), MKNK2, MLK1, PDGFRB, PLK3, RET, SNARK, SRPK3, TAK1 or TYK2 signal transduction in the subject that needs, said method comprises compound according to claim 1 from effective dose to said experimenter that use.

47. the method for an anticancer growth, said method comprises makes said cancer cell contact with compound according to claim 1 or its pharmaceutically acceptable salt.

48. one kind is to have the experimenter who needs to treat method for cancer, said method comprises compound according to claim 1 from effective dose to said experimenter or its pharmaceutically acceptable salt of using.